Adv Sci (Weinh). 2026 Oct 15:e78143. doi: 10.1002/advs.78143. Online ahead of print.
ABSTRACT
Aortic dissection (AD) is a catastrophic cardiovascular emergency triggered by severe pathological stress. While continuous stress drives vascular smooth muscle cell (VSMC) apoptosis via mitochondrial dysfunction, the precise upstream orchestrators linking these stress signals to the mitochondrial apoptotic cascade remain elusive. By integrating clinical observations and single-cell RNA sequencing, we found that Nuclear Protein 1 (Nupr1), a critical stress-responsive factor, is significantly upregulated in aortas from AD patients and murine models, with enrichment in VSMCs. Remarkably, VSMC-specific Nupr1 deficiency significantly ameliorated AD progression in vivo. Mechanistically, Nupr1 undergoes massive mitochondrial accumulation in Ang II-induced apoptotic VSMCs. Rather than operating as a conventional transcriptional regulator, mitochondrially enriched Nupr1 functions as a pathological spatial switch. It sequesters p53 within mitochondria, driving transcription-independent apoptosis while simultaneously blunting the protective Gadd45b-mediated survival program. Furthermore, in vivo Gadd45b overexpression was sufficient to rescue mitochondrial dysfunction and ameliorate vascular collapse. Taken together, our findings conceptualize the Nupr1-p53-Gadd45b axis as an important determinant of VSMC fate and provide a novel and promising therapeutic strategy for preventing AD progression.
PMID:42881547 | DOI:10.1002/advs.78143
Adv Sci (Weinh). 2026 Oct 15:e78143. doi: 10.1002/advs.78143. Online ahead of print.
ABSTRACT
Aortic dissection (AD) is a catastrophic cardiovascular emergency triggered by severe pathological stress. While continuous stress drives vascular smooth muscle cell (VSMC) apoptosis via mitochondrial dysfunction, the precise upstream orchestrators linking these stress signals to the mitochondrial apoptotic cascade remain elusive. By integrating clinical observations and single-cell RNA sequencing, we found that Nuclear Protein 1 (Nupr1), a critical stress-responsive factor, is significantly upregulated in aortas from AD patients and murine models, with enrichment in VSMCs. Remarkably, VSMC-specific Nupr1 deficiency significantly ameliorated AD progression in vivo. Mechanistically, Nupr1 undergoes massive mitochondrial accumulation in Ang II-induced apoptotic VSMCs. Rather than operating as a conventional transcriptional regulator, mitochondrially enriched Nupr1 functions as a pathological spatial switch. It sequesters p53 within mitochondria, driving transcription-independent apoptosis while simultaneously blunting the protective Gadd45b-mediated survival program. Furthermore, in vivo Gadd45b overexpression was sufficient to rescue mitochondrial dysfunction and ameliorate vascular collapse. Taken together, our findings conceptualize the Nupr1-p53-Gadd45b axis as an important determinant of VSMC fate and provide a novel and promising therapeutic strategy for preventing AD progression.
PMID:42881547 | DOI:10.1002/advs.78143
J Immunol Res. 2026;2026(1):e9860463. doi: 10.1155/jimr/9860463.
NO ABSTRACT
PMID:42866932 | PMC:PMC13659642 | DOI:10.1155/jimr/9860463
J Immunol Res. 2026;2026(1):e9860463. doi: 10.1155/jimr/9860463.
NO ABSTRACT
PMID:42866932 | PMC:PMC13659642 | DOI:10.1155/jimr/9860463
CJC Open. 2026 Jun 29;8(10):1431-1446. doi: 10.1016/j.cjco.2026.06.010. eCollection 2026 Oct.
ABSTRACT
BACKGROUND: Aortic pathologies, including abdominal aortic aneurysm, thoracic aortic aneurysm, and aortic dissection, are life-threatening conditions characterized by complex pathophysiology and a lack of simple, early, and reliable diagnostic tools.
METHODS: This review synthesizes current knowledge on the molecular and cellular mechanisms underlying aortic pathologies, with a particular focus on vascular smooth muscle cell dysfunction, extracellular matrix degradation, and inflammatory signaling pathways. The review critically evaluates the strengths and limitations of widely used murine models, including elastase infusion, calcium chloride application, angiotensin II infusion, and \u03b2-aminopropionitrile administration, in the context of current clinical knowledge.
RESULTS: Murine models provide valuable insights into the early stages of disease, which are often inaccessible in humans, and have been instrumental in elucidating key mechanisms involved in aneurysm formation and dissection. These models differ in their anatomic specificity, vascular remodelling dynamics, immune activation profiles, and translational relevance. Emerging complementary approaches, including advanced translational platforms and computational models, further improve the interpretation and translational value of preclinical findings.
CONCLUSIONS: By linking experimental findings to clinical perspectives, this review proposes a bench-to-bedside framework for the study of aortic disease. Integrating complementary experimental models with human-relevant systems may improve mechanistic understanding and support future diagnostic and therapeutic strategies innovation in aortic aneurysm and dissection.
PMID:42861284 | PMC:PMC13654332 | DOI:10.1016/j.cjco.2026.06.010
CJC Open. 2026 Jun 29;8(10):1431-1446. doi: 10.1016/j.cjco.2026.06.010. eCollection 2026 Oct.
ABSTRACT
BACKGROUND: Aortic pathologies, including abdominal aortic aneurysm, thoracic aortic aneurysm, and aortic dissection, are life-threatening conditions characterized by complex pathophysiology and a lack of simple, early, and reliable diagnostic tools.
METHODS: This review synthesizes current knowledge on the molecular and cellular mechanisms underlying aortic pathologies, with a particular focus on vascular smooth muscle cell dysfunction, extracellular matrix degradation, and inflammatory signaling pathways. The review critically evaluates the strengths and limitations of widely used murine models, including elastase infusion, calcium chloride application, angiotensin II infusion, and \u03b2-aminopropionitrile administration, in the context of current clinical knowledge.
RESULTS: Murine models provide valuable insights into the early stages of disease, which are often inaccessible in humans, and have been instrumental in elucidating key mechanisms involved in aneurysm formation and dissection. These models differ in their anatomic specificity, vascular remodelling dynamics, immune activation profiles, and translational relevance. Emerging complementary approaches, including advanced translational platforms and computational models, further improve the interpretation and translational value of preclinical findings.
CONCLUSIONS: By linking experimental findings to clinical perspectives, this review proposes a bench-to-bedside framework for the study of aortic disease. Integrating complementary experimental models with human-relevant systems may improve mechanistic understanding and support future diagnostic and therapeutic strategies innovation in aortic aneurysm and dissection.
PMID:42861284 | PMC:PMC13654332 | DOI:10.1016/j.cjco.2026.06.010
J Am Heart Assoc. 2026 Oct 10:e050327. doi: 10.1161/JAHA.126.050327. Online ahead of print.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a lethal cardiovascular emergency with a complex and underexplored genetic basis.
METHODS: We performed whole-genome sequencing on 151 patients with sporadic Stanford type B AD and 965 healthy controls in a Chinese population as a discovery phase analysis to assess both common and rare variants. Cross-ancestry meta-analyses incorporating 4 external genome-wide association data sets were used to identify population-specific risk loci. To pinpoint functional candidates, we integrated epigenomic profiles and single-cell transcriptomes from human aortic tissues.
RESULTS: Whole-genome sequencing analysis identified 21 candidate common loci and 2 low-frequency variants associated with AD in this discovery cohort. Two candidate common variants in the human leukocyte antigen region (rs9260945 near HLA-A and rs9276409 within HLA-DQA2) showed strong associations and colocalized with regulatory elements in aortic and immune cells, indicating immune-mediated vascular pathology. A low-frequency missense variant in the COG5 gene (rs1203229795, effect allele frequency=0.019) emerged as an independent AD risk factor, likely affecting extracellular matrix glycosylation. Single-cell transcriptomic analysis of AD-associated variants in human aortic tissues demonstrated enhanced interactions among fibroblasts, vascular smooth muscle cells, and macrophages, supporting their roles in AD pathogenesis. Integrated gene-based and expression analyses further highlighted TPM4, a marker of vascular smooth muscle cell dedifferentiation, as a putative susceptibility gene in AD.
CONCLUSIONS: This multiomics investigation expands the genetic landscape of sporadic AD in Chinese individuals, revealing immune-related human leukocyte antigen loci and a functionally supported candidate COG5 variant. Our findings offer new insights into AD pathogenesis and identify candidate targets for future diagnostic and therapeutic strategies.
PMID:42857991 | DOI:10.1161/JAHA.126.050327
J Am Heart Assoc. 2026 Oct 10:e050327. doi: 10.1161/JAHA.126.050327. Online ahead of print.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a lethal cardiovascular emergency with a complex and underexplored genetic basis.
METHODS: We performed whole-genome sequencing on 151 patients with sporadic Stanford type B AD and 965 healthy controls in a Chinese population as a discovery phase analysis to assess both common and rare variants. Cross-ancestry meta-analyses incorporating 4 external genome-wide association data sets were used to identify population-specific risk loci. To pinpoint functional candidates, we integrated epigenomic profiles and single-cell transcriptomes from human aortic tissues.
RESULTS: Whole-genome sequencing analysis identified 21 candidate common loci and 2 low-frequency variants associated with AD in this discovery cohort. Two candidate common variants in the human leukocyte antigen region (rs9260945 near HLA-A and rs9276409 within HLA-DQA2) showed strong associations and colocalized with regulatory elements in aortic and immune cells, indicating immune-mediated vascular pathology. A low-frequency missense variant in the COG5 gene (rs1203229795, effect allele frequency=0.019) emerged as an independent AD risk factor, likely affecting extracellular matrix glycosylation. Single-cell transcriptomic analysis of AD-associated variants in human aortic tissues demonstrated enhanced interactions among fibroblasts, vascular smooth muscle cells, and macrophages, supporting their roles in AD pathogenesis. Integrated gene-based and expression analyses further highlighted TPM4, a marker of vascular smooth muscle cell dedifferentiation, as a putative susceptibility gene in AD.
CONCLUSIONS: This multiomics investigation expands the genetic landscape of sporadic AD in Chinese individuals, revealing immune-related human leukocyte antigen loci and a functionally supported candidate COG5 variant. Our findings offer new insights into AD pathogenesis and identify candidate targets for future diagnostic and therapeutic strategies.
PMID:42857991 | DOI:10.1161/JAHA.126.050327
J Am Heart Assoc. 2026 Oct 10:e048571. doi: 10.1161/JAHA.126.048571. Online ahead of print.
ABSTRACT
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening vascular disease that lacks effective pharmacological treatment. Canonical transient receptor potential (TRPC) channels are involved in regulating various cardiovascular functions, yet their roles in TAD have not been elucidated.
METHODS: Three-week-old male mice were administered \u03b2-aminopropionitrile dissolved in drinking water for 28 days to induce TAD formation. The effects of TRPCs on TAD were explored in vitro and in vivo. RNA sequencing of thoracic aortas was performed to investigate the mechanism by which TRPCs regulate TAD progression.
RESULTS: Among the TRPC family members, TRPC1 expression was markedly increased in aortas from \u03b2-aminopropionitrile-induced TAD mice along with the downregulation of the vascular smooth muscle cell (SMC) contractile markers smooth muscle \u03b1-actin and smooth muscle 22. Compared with control littermates, SMC-specific TRPC1 deficiency in mice alleviated \u03b2-aminopropionitrile-induced TAD formation characterized by decreased aortic rupture, reduced maximal thoracic aortic diameters, and less elastin degradation. Conversely, SMC-specific knock-in of TRPC1 exacerbated TAD development in mice. Unbiased RNA sequencing showed that TRPC1 knockout in vascular SMCs inhibited the expression of inflammatory factors and chemokines in thoracic aortas during the early stage of \u03b2-aminopropionitrile administration. Mechanistically, TRPC1 induced the proinflammatory phenotypic transition of vascular SMCs by activating the calcineurin/nuclear factor-\u03baB pathway, thereby contributing to vascular inflammation and TAD development.
CONCLUSIONS: Our study identified TRPC1 as a novel endogenous pathogenic factor for vascular SMC inflammatory phenotypic transition and TAD formation and provided new insights for a comprehensive understanding of the mechanisms during TAD. Blocking the TRPC1/calcineurin/nuclear factor-\u03baB signaling suppressed TAD progression, which may be a promising strategy to address TAD.
PMID:42857971 | DOI:10.1161/JAHA.126.048571
J Am Heart Assoc. 2026 Oct 10:e048571. doi: 10.1161/JAHA.126.048571. Online ahead of print.
ABSTRACT
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening vascular disease that lacks effective pharmacological treatment. Canonical transient receptor potential (TRPC) channels are involved in regulating various cardiovascular functions, yet their roles in TAD have not been elucidated.
METHODS: Three-week-old male mice were administered \u03b2-aminopropionitrile dissolved in drinking water for 28 days to induce TAD formation. The effects of TRPCs on TAD were explored in vitro and in vivo. RNA sequencing of thoracic aortas was performed to investigate the mechanism by which TRPCs regulate TAD progression.
RESULTS: Among the TRPC family members, TRPC1 expression was markedly increased in aortas from \u03b2-aminopropionitrile-induced TAD mice along with the downregulation of the vascular smooth muscle cell (SMC) contractile markers smooth muscle \u03b1-actin and smooth muscle 22. Compared with control littermates, SMC-specific TRPC1 deficiency in mice alleviated \u03b2-aminopropionitrile-induced TAD formation characterized by decreased aortic rupture, reduced maximal thoracic aortic diameters, and less elastin degradation. Conversely, SMC-specific knock-in of TRPC1 exacerbated TAD development in mice. Unbiased RNA sequencing showed that TRPC1 knockout in vascular SMCs inhibited the expression of inflammatory factors and chemokines in thoracic aortas during the early stage of \u03b2-aminopropionitrile administration. Mechanistically, TRPC1 induced the proinflammatory phenotypic transition of vascular SMCs by activating the calcineurin/nuclear factor-\u03baB pathway, thereby contributing to vascular inflammation and TAD development.
CONCLUSIONS: Our study identified TRPC1 as a novel endogenous pathogenic factor for vascular SMC inflammatory phenotypic transition and TAD formation and provided new insights for a comprehensive understanding of the mechanisms during TAD. Blocking the TRPC1/calcineurin/nuclear factor-\u03baB signaling suppressed TAD progression, which may be a promising strategy to address TAD.
PMID:42857971 | DOI:10.1161/JAHA.126.048571
PLoS One. 2026 Oct 8;21(10):e0359784. doi: 10.1371/journal.pone.0359784. eCollection 2026.
ABSTRACT
BACKGROUND: Sepsis and thoracic aortic aneurysm (TAA) share pathological features of inflammation and vascular dysfunction, yet their molecular connections remain unclear.
METHODS: Transcriptomic datasets of sepsis and TAA from GEO were integrated to identify shared differentially expressed genes (DEGs). Functional enrichment and gene set enrichment analyses were performed to explore potential pathways. Machine learning models were applied to identify candidate genes with discriminatory potential, followed by immune infiltration analysis and assessment of gene expression in lipopolysaccharide (LPS)-treated vascular smooth muscle cells (VSMCs).
RESULTS: A total of 193 shared DEGs were identified, mainly enriched in T cell activation, Th17 differentiation, and oxidative stress-related pathways. Five candidate genes (ARG1, IL18R1, LIX1L, TRIM32, and PRKCH) were selected through sequential machine-learning analysis and showed generally reproducible expression patterns across independent datasets. Their expression was associated with estimated immune cell proportions. In LPS-treated VSMCs, ARG1 and IL18R1 were upregulated, whereas LIX1L was downregulated.
CONCLUSION: Sepsis and TAA share common transcriptional signatures involving immune dysregulation and metabolic stress. ARG1 and IL18R1 may represent candidate molecular features associated with inflammatory and vascular responses.
PMID:42848775 | PMC:PMC13649027 | DOI:10.1371/journal.pone.0359784
PLoS One. 2026 Oct 8;21(10):e0359784. doi: 10.1371/journal.pone.0359784. eCollection 2026.
ABSTRACT
BACKGROUND: Sepsis and thoracic aortic aneurysm (TAA) share pathological features of inflammation and vascular dysfunction, yet their molecular connections remain unclear.
METHODS: Transcriptomic datasets of sepsis and TAA from GEO were integrated to identify shared differentially expressed genes (DEGs). Functional enrichment and gene set enrichment analyses were performed to explore potential pathways. Machine learning models were applied to identify candidate genes with discriminatory potential, followed by immune infiltration analysis and assessment of gene expression in lipopolysaccharide (LPS)-treated vascular smooth muscle cells (VSMCs).
RESULTS: A total of 193 shared DEGs were identified, mainly enriched in T cell activation, Th17 differentiation, and oxidative stress-related pathways. Five candidate genes (ARG1, IL18R1, LIX1L, TRIM32, and PRKCH) were selected through sequential machine-learning analysis and showed generally reproducible expression patterns across independent datasets. Their expression was associated with estimated immune cell proportions. In LPS-treated VSMCs, ARG1 and IL18R1 were upregulated, whereas LIX1L was downregulated.
CONCLUSION: Sepsis and TAA share common transcriptional signatures involving immune dysregulation and metabolic stress. ARG1 and IL18R1 may represent candidate molecular features associated with inflammatory and vascular responses.
PMID:42848775 | PMC:PMC13649027 | DOI:10.1371/journal.pone.0359784
Commun Biol. 2026 Sep 21;9(1):1289. doi: 10.1038/s42003-026-10871-z.
ABSTRACT
Aortic dissection is a life-threatening cardiovascular emergency characterized by rapid progression and high mortality. Although medial degeneration is a key pathological feature of aortic dissection, the mechanisms that drive aortic wall instability remain incompletely understood. Aortic calcification is a pathological mineralization process that can alter vascular structure and function, but its role in aortic dissection has received limited attention. Here we show that tissue nonspecific alkaline phosphatase associated calcium phosphate microdeposition is linked to aortic medial degeneration and dissection susceptibility. Human aortic dissection tissues and diseased mouse aortas show increased mineralization together with elevated tissue nonspecific alkaline phosphatase activity. Calcium phosphate deposits promote vascular smooth muscle cell phenotypic switching and inflammatory remodeling, while tissue nonspecific alkaline phosphatase facilitates mineral deposition under permissive conditions. Reducing tissue nonspecific alkaline phosphatase activity or expression attenuates aortic calcium phosphate deposition, medial degeneration and dissection in mice. These findings identify tissue nonspecific alkaline phosphatase associated microdeposition as a mechanism contributing to aortic wall vulnerability.
PMID:42834101 | PMC:PMC13639094 | DOI:10.1038/s42003-026-10871-z
Commun Biol. 2026 Sep 21;9(1):1289. doi: 10.1038/s42003-026-10871-z.
ABSTRACT
Aortic dissection is a life-threatening cardiovascular emergency characterized by rapid progression and high mortality. Although medial degeneration is a key pathological feature of aortic dissection, the mechanisms that drive aortic wall instability remain incompletely understood. Aortic calcification is a pathological mineralization process that can alter vascular structure and function, but its role in aortic dissection has received limited attention. Here we show that tissue nonspecific alkaline phosphatase associated calcium phosphate microdeposition is linked to aortic medial degeneration and dissection susceptibility. Human aortic dissection tissues and diseased mouse aortas show increased mineralization together with elevated tissue nonspecific alkaline phosphatase activity. Calcium phosphate deposits promote vascular smooth muscle cell phenotypic switching and inflammatory remodeling, while tissue nonspecific alkaline phosphatase facilitates mineral deposition under permissive conditions. Reducing tissue nonspecific alkaline phosphatase activity or expression attenuates aortic calcium phosphate deposition, medial degeneration and dissection in mice. These findings identify tissue nonspecific alkaline phosphatase associated microdeposition as a mechanism contributing to aortic wall vulnerability.
PMID:42834101 | PMC:PMC13639094 | DOI:10.1038/s42003-026-10871-z
ACS Omega. 2026 Aug 17;11(34):50992-51003. doi: 10.1021/acsomega.6c02956. eCollection 2026 Sep 1.
ABSTRACT
Aortic dissection (AD) is a life-threatening cardiovascular disease with an extremely high mortality rate. Excessive reactive oxygen species (ROS) production and inflammatory responses in diseased vascular regions are central drivers of AD pathogenesis, leading to destruction of the aortic wall structure and fatal hemorrhage. However, conventional clinical therapies for AD cannot effectively eliminate excessive ROS at lesion sites while simultaneously exerting anti-inflammatory effects. To address these limitations, we developed a biomimetic, inflammation-targeting nanoparticle, ZIF-8@Res@PEG-FA (ZRF), to attenuate AD progression through potent antioxidant and anti-inflammatory interventions. ZRF is constructed with ZIF-8 as the core carrier, loaded with the antioxidant and anti-inflammatory agent resveratrol, and surface-modified with PEG-folic acid (PEG-FA). This nanoparticle enhances resveratrol bioavailability and leverages the inflammation-targeting capability of folic acid to preferentially accumulate in AD lesions. Under mildly acidic conditions, ZRF rapidly degrades and efficiently scavenges ROS, disrupting the oxidative stress-inflammation vicious cycle and promoting the polarization of pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype. Notably, ZRF also preserves the contractile phenotype of vascular smooth muscle cells (VSMCs), maintains extracellular matrix stability, and thereby delays AD progression. This study presents a promising therapeutic strategy for aortic dissection and other inflammatory vascular diseases.
PMID:42819177 | PMC:PMC13625157 | DOI:10.1021/acsomega.6c02956
ACS Omega. 2026 Aug 17;11(34):50992-51003. doi: 10.1021/acsomega.6c02956. eCollection 2026 Sep 1.
ABSTRACT
Aortic dissection (AD) is a life-threatening cardiovascular disease with an extremely high mortality rate. Excessive reactive oxygen species (ROS) production and inflammatory responses in diseased vascular regions are central drivers of AD pathogenesis, leading to destruction of the aortic wall structure and fatal hemorrhage. However, conventional clinical therapies for AD cannot effectively eliminate excessive ROS at lesion sites while simultaneously exerting anti-inflammatory effects. To address these limitations, we developed a biomimetic, inflammation-targeting nanoparticle, ZIF-8@Res@PEG-FA (ZRF), to attenuate AD progression through potent antioxidant and anti-inflammatory interventions. ZRF is constructed with ZIF-8 as the core carrier, loaded with the antioxidant and anti-inflammatory agent resveratrol, and surface-modified with PEG-folic acid (PEG-FA). This nanoparticle enhances resveratrol bioavailability and leverages the inflammation-targeting capability of folic acid to preferentially accumulate in AD lesions. Under mildly acidic conditions, ZRF rapidly degrades and efficiently scavenges ROS, disrupting the oxidative stress-inflammation vicious cycle and promoting the polarization of pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype. Notably, ZRF also preserves the contractile phenotype of vascular smooth muscle cells (VSMCs), maintains extracellular matrix stability, and thereby delays AD progression. This study presents a promising therapeutic strategy for aortic dissection and other inflammatory vascular diseases.
PMID:42819177 | PMC:PMC13625157 | DOI:10.1021/acsomega.6c02956
Int J Mol Sci. 2026 Sep 16;27(18):8250. doi: 10.3390/ijms27188250.
ABSTRACT
Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR1 and ADAR2, is an epitranscriptomic mechanism with emerging roles in cardiovascular disease. We investigated ADAR expression, clinical correlates, A-to-I RNA editing signatures, transcriptome and miRNA targetome in thoracic aortic aneurysm (TAA), focusing on Marfan syndrome (MFS). Immunohistochemical analysis of 58 TAA specimens (18 MFS-associated TAA, 19 tricuspid aortic valve-associated TAA (TAV), 21 bicuspid aortic valve-associated TAA (BAV)) showed the highest ADAR1 and ADAR2 in MFS. ADAR2 in vascular smooth muscle cells (vSMCs) correlated positively with aortic diameter across subtypes; ADAR1 inversely correlated with sinotubular junction dimension in MFS. Transcriptomic profiling of MFS-derived vSMC cultures identified 30 differentially expressed genes enriched in immune activation, impaired RTK signaling, and vSMC reprogramming. RNA editing analysis revealed 77 differentially edited sites across 65 genes, predominantly hypoedited in MFS, including four protein-coding recoding events at PPIL3, SLC12A6, CTSB, and VHL. miRNA seed-match analysis of 47 significant 3'UTR sites predicted 458 editing-dependent interactions across 36 genes. Only 14/36 genes showed concordant mRNA changes, suggesting that editing-dependent miRNA retargeting acts primarily at the translational level. These findings establish ADAR enzymes as candidates tissue biomarkers of TAA severity and ADAR1 as the principal driver of epitranscriptomic dysregulation in MFS aortopathy.
PMID:42794678 | PMC:PMC13607941 | DOI:10.3390/ijms27188250
Int J Mol Sci. 2026 Sep 16;27(18):8250. doi: 10.3390/ijms27188250.
ABSTRACT
Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR1 and ADAR2, is an epitranscriptomic mechanism with emerging roles in cardiovascular disease. We investigated ADAR expression, clinical correlates, A-to-I RNA editing signatures, transcriptome and miRNA targetome in thoracic aortic aneurysm (TAA), focusing on Marfan syndrome (MFS). Immunohistochemical analysis of 58 TAA specimens (18 MFS-associated TAA, 19 tricuspid aortic valve-associated TAA (TAV), 21 bicuspid aortic valve-associated TAA (BAV)) showed the highest ADAR1 and ADAR2 in MFS. ADAR2 in vascular smooth muscle cells (vSMCs) correlated positively with aortic diameter across subtypes; ADAR1 inversely correlated with sinotubular junction dimension in MFS. Transcriptomic profiling of MFS-derived vSMC cultures identified 30 differentially expressed genes enriched in immune activation, impaired RTK signaling, and vSMC reprogramming. RNA editing analysis revealed 77 differentially edited sites across 65 genes, predominantly hypoedited in MFS, including four protein-coding recoding events at PPIL3, SLC12A6, CTSB, and VHL. miRNA seed-match analysis of 47 significant 3'UTR sites predicted 458 editing-dependent interactions across 36 genes. Only 14/36 genes showed concordant mRNA changes, suggesting that editing-dependent miRNA retargeting acts primarily at the translational level. These findings establish ADAR enzymes as candidates tissue biomarkers of TAA severity and ADAR1 as the principal driver of epitranscriptomic dysregulation in MFS aortopathy.
PMID:42794678 | PMC:PMC13607941 | DOI:10.3390/ijms27188250
Biomedicines. 2026 Sep 14;14(9):2061. doi: 10.3390/biomedicines14092061.
ABSTRACT
Background: Aortic dissection (AD) is a life-threatening vascular disease with high mortality, yet its molecular pathogenesis remains incompletely understood. This study investigated the role of regulated in development and DNA damage responses 1 (REDD1) in vascular smooth muscle cells (VSMCs) apoptosis and the underlying mechanisms. Methods: Single-cell RNA sequencing data from GSE222318 were analyzed to investigate the expression levels of REDD1 in VSMCs and its role in inducing apoptosis and autophagy. The target gene was silenced in C57BL/6J mice via tail-vein injection of Adeno-associated virus.\u03b2-aminopropionitrile (BAPN) was used for AD induction. Western blotting was used to assess REDD1, LC3B, p62, BAX, BCL-2 in aortic tissues. Aortic histopathological alterations were examined by hematoxylin and eosin (H&E), Elastica van Gieson (EVG), and Masson's trichrome staining. Immunofluorescence was performed to examine REDD1 expression and its localization in \u03b1-SMA-positive vascular smooth muscle cells. REDD1, LC3B, p62, BAX, BCL-2, mTOR, and p-mTOR were also examined by Western blotting in cultured cells. Mitochondrial membrane potential was evaluated by JC-1 staining, and apoptosis was assessed by flow cytometry. Results: REDD1 expression levels were significantly increased in human AD tissues and localized predominantly to medial VSMCs. REDD1 levels were positively correlated with BAX and LC3B and negatively correlated with BCL-2 and p62. Knockdown of REDD1 in AD mice was associated with increased levels of BAX and p62 and decreased levels of BCL-2 and LC3B in aortic tissues, accompanied by more severe pathological manifestations. REDD1 silencing in VSMCs increased BAX, p62 and p-mTOR while reducing BCL-2 and LC3B, accompanied by increased apoptosis and loss of mitochondrial membrane potential, whereas rapamycin reduced apoptosis and alleviated mitochondrial injury. Conclusions: REDD1 appears to play a protective, compensatory role in AD. Increased REDD1 expression may help preserve mitochondrial membrane potential and attenuate VSMC apoptosis under pathological stress, accompanied by changes in static autophagy-related markers that suggest a possible association with increased autophagic activity. Loss of REDD1 activity promotes mitochondrial injury and VSMC apoptosis, thereby aggravating AD. Targeting REDD1 may therefore represent a potential therapeutic strategy for AD.
PMID:42792802 | PMC:PMC13604472 | DOI:10.3390/biomedicines14092061
Biomedicines. 2026 Sep 14;14(9):2061. doi: 10.3390/biomedicines14092061.
ABSTRACT
Background: Aortic dissection (AD) is a life-threatening vascular disease with high mortality, yet its molecular pathogenesis remains incompletely understood. This study investigated the role of regulated in development and DNA damage responses 1 (REDD1) in vascular smooth muscle cells (VSMCs) apoptosis and the underlying mechanisms. Methods: Single-cell RNA sequencing data from GSE222318 were analyzed to investigate the expression levels of REDD1 in VSMCs and its role in inducing apoptosis and autophagy. The target gene was silenced in C57BL/6J mice via tail-vein injection of Adeno-associated virus.\u03b2-aminopropionitrile (BAPN) was used for AD induction. Western blotting was used to assess REDD1, LC3B, p62, BAX, BCL-2 in aortic tissues. Aortic histopathological alterations were examined by hematoxylin and eosin (H&E), Elastica van Gieson (EVG), and Masson's trichrome staining. Immunofluorescence was performed to examine REDD1 expression and its localization in \u03b1-SMA-positive vascular smooth muscle cells. REDD1, LC3B, p62, BAX, BCL-2, mTOR, and p-mTOR were also examined by Western blotting in cultured cells. Mitochondrial membrane potential was evaluated by JC-1 staining, and apoptosis was assessed by flow cytometry. Results: REDD1 expression levels were significantly increased in human AD tissues and localized predominantly to medial VSMCs. REDD1 levels were positively correlated with BAX and LC3B and negatively correlated with BCL-2 and p62. Knockdown of REDD1 in AD mice was associated with increased levels of BAX and p62 and decreased levels of BCL-2 and LC3B in aortic tissues, accompanied by more severe pathological manifestations. REDD1 silencing in VSMCs increased BAX, p62 and p-mTOR while reducing BCL-2 and LC3B, accompanied by increased apoptosis and loss of mitochondrial membrane potential, whereas rapamycin reduced apoptosis and alleviated mitochondrial injury. Conclusions: REDD1 appears to play a protective, compensatory role in AD. Increased REDD1 expression may help preserve mitochondrial membrane potential and attenuate VSMC apoptosis under pathological stress, accompanied by changes in static autophagy-related markers that suggest a possible association with increased autophagic activity. Loss of REDD1 activity promotes mitochondrial injury and VSMC apoptosis, thereby aggravating AD. Targeting REDD1 may therefore represent a potential therapeutic strategy for AD.
PMID:42792802 | PMC:PMC13604472 | DOI:10.3390/biomedicines14092061
J Am Heart Assoc. 2026 Oct 6;15(19):e047767. doi: 10.1161/JAHA.125.047767. Epub 2026 Sep 24.
ABSTRACT
BACKGROUND: The pathogenesis of thoracic aortic dissection (TAD) involves phenotypic switching of vascular smooth muscle cells (VSMCs) and VSMCs apoptosis. PXR (pregnane X receptor) is a known regulator of apoptosis. The mechanistic role of PXR in the pathogenesis of TAD remains elusive.
METHODS: Microarray data sets related to TAD were obtained from the Gene Expression Omnibus database to identify differentially expressed genes. Four-week-old male Pxr-overexpressing mice, beta carotene-treated mice, and Ldha-knockdown mice were administered \u03b2-aminopropionitrile (1 g/kg per day) in drinking water for 4 weeks, followed by intraperitoneal injection of angiotensin II (1.44 mg/kg 3 times daily) for 3 days to induce TAD. Lactate concentration and lactate dehydrogenase activity were measured using commercially available assay kits. Apoptosis was assessed by TUNEL staining. VSMC phenotype transformation was detected by quantitative real-time polymerase chain reaction, immunofluorescence, and western blot.
RESULTS: Microarray analysis of data sets from the Gene Expression Omnibus revealed downregulated PXR expression in aortic tissues from TAD patients. Consistently, reduced PXR expression was observed in aortic tissues from both TAD patients and \u03b2-aminopropionitrile-induced TAD mice. \u03b2-Aminopropionitrile-induced TAD progression was significantly ameliorated in mice with PXR overexpression or activation. PXR activation effectively suppressed VSMCs phenotypic switching. It also inhibited LDHA expression, thereby reducing lactate accumulation, attenuating VSMC apoptosis, and ultimately alleviating TAD progression. In line with these findings, \u03b2-aminopropionitrile-induced TAD progression was significantly ameliorated in Ldha-knockdown mice.
CONCLUSIONS: PXR signaling may represent a novel target for the prevention and treatment of TAD.
PMID:42786635 | DOI:10.1161/JAHA.125.047767
J Am Heart Assoc. 2026 Oct 6;15(19):e047767. doi: 10.1161/JAHA.125.047767. Epub 2026 Sep 24.
ABSTRACT
BACKGROUND: The pathogenesis of thoracic aortic dissection (TAD) involves phenotypic switching of vascular smooth muscle cells (VSMCs) and VSMCs apoptosis. PXR (pregnane X receptor) is a known regulator of apoptosis. The mechanistic role of PXR in the pathogenesis of TAD remains elusive.
METHODS: Microarray data sets related to TAD were obtained from the Gene Expression Omnibus database to identify differentially expressed genes. Four-week-old male Pxr-overexpressing mice, beta carotene-treated mice, and Ldha-knockdown mice were administered \u03b2-aminopropionitrile (1 g/kg per day) in drinking water for 4 weeks, followed by intraperitoneal injection of angiotensin II (1.44 mg/kg 3 times daily) for 3 days to induce TAD. Lactate concentration and lactate dehydrogenase activity were measured using commercially available assay kits. Apoptosis was assessed by TUNEL staining. VSMC phenotype transformation was detected by quantitative real-time polymerase chain reaction, immunofluorescence, and western blot.
RESULTS: Microarray analysis of data sets from the Gene Expression Omnibus revealed downregulated PXR expression in aortic tissues from TAD patients. Consistently, reduced PXR expression was observed in aortic tissues from both TAD patients and \u03b2-aminopropionitrile-induced TAD mice. \u03b2-Aminopropionitrile-induced TAD progression was significantly ameliorated in mice with PXR overexpression or activation. PXR activation effectively suppressed VSMCs phenotypic switching. It also inhibited LDHA expression, thereby reducing lactate accumulation, attenuating VSMC apoptosis, and ultimately alleviating TAD progression. In line with these findings, \u03b2-aminopropionitrile-induced TAD progression was significantly ameliorated in Ldha-knockdown mice.
CONCLUSIONS: PXR signaling may represent a novel target for the prevention and treatment of TAD.
PMID:42786635 | DOI:10.1161/JAHA.125.047767
Biochem Pharmacol. 2026 Sep 16;254(Pt 2):118484. doi: 10.1016/j.bcp.2026.118484. Online ahead of print.
ABSTRACT
Colchicine is a traditional plant alkaloid extracted from the seeds and bulbs of the colchicum plant, exhibiting potent anti-inflammatory effects. It is currently widely used clinically for the acute treatment of gouty arthritis. Aortic dissection is a life-threatening acute aortic syndrome whose pathogenesis remains incompletely elucidated; however, the prevailing view holds that phenotypic transformation of aortic smooth muscle cells and inflammatory responses play crucial roles. Colchicine has demonstrated anti-inflammatory and antioxidant properties; however, its precise mechanism of action in aortic dissection remains unclear. This study investigated colchicine's role in aortic dissection by establishing a mouse aortic dissection/aneurysm model and employing rat primary smooth muscle cells in in vitro experiments. Our findings reveal that colchicine effectively reduces the incidence of aortic dissection, mitigates aortic inflammation in mice, and inhibits aortic smooth muscle cell phenotypic conversion. Transcriptomic sequencing results indicate the IL17A/17RA pathway plays a pivotal role in these processes, suggesting a novel potential pathway for the pathogenesis of aortic dissection and offering a new therapeutic candidate.
PMID:42749231 | DOI:10.1016/j.bcp.2026.118484
Biochem Pharmacol. 2026 Sep 16;254(Pt 2):118484. doi: 10.1016/j.bcp.2026.118484. Online ahead of print.
ABSTRACT
Colchicine is a traditional plant alkaloid extracted from the seeds and bulbs of the colchicum plant, exhibiting potent anti-inflammatory effects. It is currently widely used clinically for the acute treatment of gouty arthritis. Aortic dissection is a life-threatening acute aortic syndrome whose pathogenesis remains incompletely elucidated; however, the prevailing view holds that phenotypic transformation of aortic smooth muscle cells and inflammatory responses play crucial roles. Colchicine has demonstrated anti-inflammatory and antioxidant properties; however, its precise mechanism of action in aortic dissection remains unclear. This study investigated colchicine's role in aortic dissection by establishing a mouse aortic dissection/aneurysm model and employing rat primary smooth muscle cells in in vitro experiments. Our findings reveal that colchicine effectively reduces the incidence of aortic dissection, mitigates aortic inflammation in mice, and inhibits aortic smooth muscle cell phenotypic conversion. Transcriptomic sequencing results indicate the IL17A/17RA pathway plays a pivotal role in these processes, suggesting a novel potential pathway for the pathogenesis of aortic dissection and offering a new therapeutic candidate.
PMID:42749231 | DOI:10.1016/j.bcp.2026.118484
Front Cardiovasc Med. 2026 Aug 31;13:1822129. doi: 10.3389/fcvm.2026.1822129. eCollection 2026.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a catastrophic cardiovascular emergency with high morbidity and mortality. Despite advances in diagnosis and treatment, its complex pathogenesis, optimal therapies, and postoperative complications remain major challenges. Although AD research has expanded substantially, quantitative analyses integrating global knowledge structures with molecular mechanisms remain limited. This study mapped the development, contributors, hotspots, and emerging frontiers of global AD research to support future investigation and clinical translation.
METHODS: AD-related literature published from January 1, 2000, to December 31, 2025, was retrieved from the Web of Science Core Collection and Scopus. Excel, VOSviewer, CiteSpace, Scimago Graphica, and bibliometrix were used for bibliometric analyses, and a logistic growth model characterized publication trends. Single-cell RNA sequencing datasets GSE254132 and GSE213740 served as discovery and external-validation cohorts, respectively. Seurat, Harmony, donor-level pseudobulk differential expression, and exact donor-label permutation tests were applied. Differentially expressed genes were linked to target-specific PubMed trajectories to distinguish established AD genes from literature-sparse candidates.
RESULTS: A total of 5,170 publications were included. Output accelerated after 2010 and reached 712 articles in 2025. China produced the most publications, whereas the United States had the highest citation count and strongest international collaboration. Four convergent frontiers emerged: endovascular therapy, inflammation and vascular-wall remodeling, candidate molecular markers, and machine-learning-based prognosis. In GSE254132, AD was associated with vascular smooth muscle cell remodeling and a higher proportion of SPP1\u207a remodeling macrophages. GSE213740 reproduced the direction of this remodeling program and showed a smaller increase in SPP1\u207a macrophages despite compositional differences. During 2000-2025, PubMed indexed 1,483 publications on angiopoietin-like 4 (ANGPTL4) and 240 on matrix metalloproteinase 19 (MMP19) across biomedical fields. Output increased by 49.9% and 43.5%, respectively, in 2021-2025 versus 2016-2020. Record-level screening identified only two original AD-relevant publications for each target.
CONCLUSION: This study maps the global structure and changing priorities of AD research and uses human single-cell data as a biological cross-check and candidate-prioritization layer. The combined evidence identifies ANGPTL4 and MMP19 as literature-sparse molecules that warrant mechanistic investigation, not as validated therapeutic targets. Independent cohorts and functional experiments are required before either molecule can be assigned diagnostic or therapeutic value.
PMID:42741187 | PMC:PMC13572280 | DOI:10.3389/fcvm.2026.1822129
Front Cardiovasc Med. 2026 Aug 31;13:1822129. doi: 10.3389/fcvm.2026.1822129. eCollection 2026.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a catastrophic cardiovascular emergency with high morbidity and mortality. Despite advances in diagnosis and treatment, its complex pathogenesis, optimal therapies, and postoperative complications remain major challenges. Although AD research has expanded substantially, quantitative analyses integrating global knowledge structures with molecular mechanisms remain limited. This study mapped the development, contributors, hotspots, and emerging frontiers of global AD research to support future investigation and clinical translation.
METHODS: AD-related literature published from January 1, 2000, to December 31, 2025, was retrieved from the Web of Science Core Collection and Scopus. Excel, VOSviewer, CiteSpace, Scimago Graphica, and bibliometrix were used for bibliometric analyses, and a logistic growth model characterized publication trends. Single-cell RNA sequencing datasets GSE254132 and GSE213740 served as discovery and external-validation cohorts, respectively. Seurat, Harmony, donor-level pseudobulk differential expression, and exact donor-label permutation tests were applied. Differentially expressed genes were linked to target-specific PubMed trajectories to distinguish established AD genes from literature-sparse candidates.
RESULTS: A total of 5,170 publications were included. Output accelerated after 2010 and reached 712 articles in 2025. China produced the most publications, whereas the United States had the highest citation count and strongest international collaboration. Four convergent frontiers emerged: endovascular therapy, inflammation and vascular-wall remodeling, candidate molecular markers, and machine-learning-based prognosis. In GSE254132, AD was associated with vascular smooth muscle cell remodeling and a higher proportion of SPP1\u207a remodeling macrophages. GSE213740 reproduced the direction of this remodeling program and showed a smaller increase in SPP1\u207a macrophages despite compositional differences. During 2000-2025, PubMed indexed 1,483 publications on angiopoietin-like 4 (ANGPTL4) and 240 on matrix metalloproteinase 19 (MMP19) across biomedical fields. Output increased by 49.9% and 43.5%, respectively, in 2021-2025 versus 2016-2020. Record-level screening identified only two original AD-relevant publications for each target.
CONCLUSION: This study maps the global structure and changing priorities of AD research and uses human single-cell data as a biological cross-check and candidate-prioritization layer. The combined evidence identifies ANGPTL4 and MMP19 as literature-sparse molecules that warrant mechanistic investigation, not as validated therapeutic targets. Independent cohorts and functional experiments are required before either molecule can be assigned diagnostic or therapeutic value.
PMID:42741187 | PMC:PMC13572280 | DOI:10.3389/fcvm.2026.1822129
Cells. 2026 Sep 7;15(17):1624. doi: 10.3390/cells15171624.
ABSTRACT
Vascular smooth muscle cells (VSMCs) exhibit remarkable phenotypic plasticity, dynamically transitioning from a quiescent contractile state to a dedifferentiated synthetic phenotype that constitutes the fundamental cytological driver of pathological vascular remodeling in cardiovascular diseases (CVDs) including atherosclerosis, vascular restenosis, aortic dissection (AD), and vascular calcification (VC). Signal transducer and activator of transcription 3 (STAT3) operates as a master transcriptional and functional convergence node, integrating diverse upstream biochemical stimuli, neurohumoral factors, and biomechanical stressors to govern downstream gene regulatory networks. Aberrant STAT3 activation orchestrates VSMC phenotypic modulation, excessive proliferation, directional migration, programmed cell death involving apoptosis resistance and pyroptosis initiation, extracellular matrix (ECM) reorganization, and glycolytic metabolic reprogramming via canonical nuclear transcription and non-canonical subcellular actions. Here, we systematically delineate the modular structural organization, post-translational modifications, and negative regulatory feedback mechanisms of STAT3 in shaping VSMC functionality. Furthermore, we synthesize recent advances in pharmacological interventions by comprehensively categorizing therapeutic modalities into direct structural-domain inhibitors, upstream kinase-targeted indirect agents, bioactive natural products, and emerging clinical-stage translational candidates. Finally, we critically address translational hurdles regarding on-target systemic toxicities, and highlight site-specific vascular delivery systems alongside localized drug-eluting vascular devices to advance precision STAT3-targeted cardiovascular therapeutics.
PMID:42738917 | PMC:PMC13564690 | DOI:10.3390/cells15171624
Cells. 2026 Sep 7;15(17):1624. doi: 10.3390/cells15171624.
ABSTRACT
Vascular smooth muscle cells (VSMCs) exhibit remarkable phenotypic plasticity, dynamically transitioning from a quiescent contractile state to a dedifferentiated synthetic phenotype that constitutes the fundamental cytological driver of pathological vascular remodeling in cardiovascular diseases (CVDs) including atherosclerosis, vascular restenosis, aortic dissection (AD), and vascular calcification (VC). Signal transducer and activator of transcription 3 (STAT3) operates as a master transcriptional and functional convergence node, integrating diverse upstream biochemical stimuli, neurohumoral factors, and biomechanical stressors to govern downstream gene regulatory networks. Aberrant STAT3 activation orchestrates VSMC phenotypic modulation, excessive proliferation, directional migration, programmed cell death involving apoptosis resistance and pyroptosis initiation, extracellular matrix (ECM) reorganization, and glycolytic metabolic reprogramming via canonical nuclear transcription and non-canonical subcellular actions. Here, we systematically delineate the modular structural organization, post-translational modifications, and negative regulatory feedback mechanisms of STAT3 in shaping VSMC functionality. Furthermore, we synthesize recent advances in pharmacological interventions by comprehensively categorizing therapeutic modalities into direct structural-domain inhibitors, upstream kinase-targeted indirect agents, bioactive natural products, and emerging clinical-stage translational candidates. Finally, we critically address translational hurdles regarding on-target systemic toxicities, and highlight site-specific vascular delivery systems alongside localized drug-eluting vascular devices to advance precision STAT3-targeted cardiovascular therapeutics.
PMID:42738917 | PMC:PMC13564690 | DOI:10.3390/cells15171624
J Thorac Dis. 2026 Aug 31;18(8):944. doi: 10.21037/jtd-2026-1879. Epub 2026 Aug 28.
ABSTRACT
BACKGROUND: The development and progression of thoracic aortic aneurysm (TAA) are closely related to vascular smooth muscle cell (VSMC) apoptosis, oxidative stress, and phenotypic transformation. This study investigated the role of fibroblast growth factor 18 (FGF18) in angiotensin II (Ang II)-induced TAA and its underlying mechanisms.
METHODS: An in vitro Ang II-induced VSMC injury model was established, and TAA-related candidate genes were screened from GSE83675 via bioinformatics analysis. VSMCs were subsequently treated with recombinant FGF18 or small interfering RNA targeting FGF18 (si-FGF18), and cell viability, apoptosis, reactive oxygen species (ROS) levels, and phenotypic markers were assessed. Activation of fibroblast growth factor receptor 2 (FGFR2)-extracellular signal-regulated kinase (ERK)/AKT-glycogen synthase kinase 3\u03b2 (GSK3\u03b2)/\u03b2-catenin signaling was examined via subcellular fractionation, immunofluorescence, and T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) luciferase reporter assays. Pharmacological modulators, including the AKT activator SC79 and the \u03b2-catenin activator SKL2001, were used to validate pathway involvement.
RESULTS: Ang II induced dose-dependent apoptosis in VSMCs. Bioinformatics analysis identified FGF18 as an upregulated hub gene in TAA-related datasets, which was further confirmed in Ang II-treated VSMCs. Functional assays demonstrated that recombinant FGF18 aggravated Ang II-induced apoptosis, reduced cell viability, and enhanced oxidative stress, whereas FGF18 knockdown exerted protective effects. Moreover, FGF18 promoted phenotypic switching of VSMCs from a contractile to a synthetic state. Mechanistically, FGF18 activated the FGFR2-ERK/AKT signaling pathway, leading to the phosphorylation of GSK3\u03b2 and subsequent nuclear translocation of \u03b2-catenin. Pharmacological activation of AKT or \u03b2-catenin reversed the inhibitory effects of FGF18 silencing.
CONCLUSIONS: FGF18 is upregulated in Ang II-induced TAA and promotes VSMC apoptosis, oxidative stress, and phenotypic transformation from a contractile to synthetic type by activating the FGFR-ERK/AKT-GSK3\u03b2/\u03b2-catenin signaling pathway, suggesting a potential role of FGF18 in TAA-associated vascular remodeling.
PMID:42724301 | PMC:PMC13559350 | DOI:10.21037/jtd-2026-1879
J Thorac Dis. 2026 Aug 31;18(8):944. doi: 10.21037/jtd-2026-1879. Epub 2026 Aug 28.
ABSTRACT
BACKGROUND: The development and progression of thoracic aortic aneurysm (TAA) are closely related to vascular smooth muscle cell (VSMC) apoptosis, oxidative stress, and phenotypic transformation. This study investigated the role of fibroblast growth factor 18 (FGF18) in angiotensin II (Ang II)-induced TAA and its underlying mechanisms.
METHODS: An in vitro Ang II-induced VSMC injury model was established, and TAA-related candidate genes were screened from GSE83675 via bioinformatics analysis. VSMCs were subsequently treated with recombinant FGF18 or small interfering RNA targeting FGF18 (si-FGF18), and cell viability, apoptosis, reactive oxygen species (ROS) levels, and phenotypic markers were assessed. Activation of fibroblast growth factor receptor 2 (FGFR2)-extracellular signal-regulated kinase (ERK)/AKT-glycogen synthase kinase 3\u03b2 (GSK3\u03b2)/\u03b2-catenin signaling was examined via subcellular fractionation, immunofluorescence, and T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) luciferase reporter assays. Pharmacological modulators, including the AKT activator SC79 and the \u03b2-catenin activator SKL2001, were used to validate pathway involvement.
RESULTS: Ang II induced dose-dependent apoptosis in VSMCs. Bioinformatics analysis identified FGF18 as an upregulated hub gene in TAA-related datasets, which was further confirmed in Ang II-treated VSMCs. Functional assays demonstrated that recombinant FGF18 aggravated Ang II-induced apoptosis, reduced cell viability, and enhanced oxidative stress, whereas FGF18 knockdown exerted protective effects. Moreover, FGF18 promoted phenotypic switching of VSMCs from a contractile to a synthetic state. Mechanistically, FGF18 activated the FGFR2-ERK/AKT signaling pathway, leading to the phosphorylation of GSK3\u03b2 and subsequent nuclear translocation of \u03b2-catenin. Pharmacological activation of AKT or \u03b2-catenin reversed the inhibitory effects of FGF18 silencing.
CONCLUSIONS: FGF18 is upregulated in Ang II-induced TAA and promotes VSMC apoptosis, oxidative stress, and phenotypic transformation from a contractile to synthetic type by activating the FGFR-ERK/AKT-GSK3\u03b2/\u03b2-catenin signaling pathway, suggesting a potential role of FGF18 in TAA-associated vascular remodeling.
PMID:42724301 | PMC:PMC13559350 | DOI:10.21037/jtd-2026-1879
Mol Biol Rep. 2026 Sep 10;53(1):1560. doi: 10.1007/s11033-026-12538-8.
ABSTRACT
Aortic dissection (AD) is an acute cardiovascular emergency characterized by rapid progression and an extremely high risk of mortality. Its fundamental pathological process begins with an intimal tear, through which blood enters the medial layer to form a false lumen, leading to structural destabilization of the aortic wall, impaired organ perfusion, and an increased risk of rupture. In recent years, with the continued advancement of multi-omics sequencing technologies, the initiation and progression of AD have no longer been regarded merely as a consequence of hemodynamic injury. Instead, AD is now recognized as a complex pathological process driven by vascular smooth muscle cell (VSMC) loss, phenotypic remodeling, extracellular matrix (ECM) degradation, inflammatory amplification, and redox imbalance. Within this framework, programmed cell death (PCD) has emerged as a pivotal molecular hub linking structural destruction to intracellular dysregulation. Accumulating evidence indicates that multiple forms of PCD are involved in AD progression and interact with oxidative stress, mitochondrial dysfunction, immune cell infiltration, and matrix metalloproteinase activation to form a mutually reinforcing injury network. At present, the clinical management of AD still centers on rapid imaging-based diagnosisand timely standardized intervention, including intensive blood pressure and heart rate control, open surgical repair, and endovascular repair. Although substantial progress has been made in elucidating the mechanisms of PCD, clinical translational evidence for precision therapies targeting specific cell death pathways remains limited. Therefore, this review summarizes the mechanistic roles of PCD in AD and integrates these insights with emerging strategies for early diagnosis and precision treatment.
PMID:42720823 | DOI:10.1007/s11033-026-12538-8
Mol Biol Rep. 2026 Sep 10;53(1):1560. doi: 10.1007/s11033-026-12538-8.
ABSTRACT
Aortic dissection (AD) is an acute cardiovascular emergency characterized by rapid progression and an extremely high risk of mortality. Its fundamental pathological process begins with an intimal tear, through which blood enters the medial layer to form a false lumen, leading to structural destabilization of the aortic wall, impaired organ perfusion, and an increased risk of rupture. In recent years, with the continued advancement of multi-omics sequencing technologies, the initiation and progression of AD have no longer been regarded merely as a consequence of hemodynamic injury. Instead, AD is now recognized as a complex pathological process driven by vascular smooth muscle cell (VSMC) loss, phenotypic remodeling, extracellular matrix (ECM) degradation, inflammatory amplification, and redox imbalance. Within this framework, programmed cell death (PCD) has emerged as a pivotal molecular hub linking structural destruction to intracellular dysregulation. Accumulating evidence indicates that multiple forms of PCD are involved in AD progression and interact with oxidative stress, mitochondrial dysfunction, immune cell infiltration, and matrix metalloproteinase activation to form a mutually reinforcing injury network. At present, the clinical management of AD still centers on rapid imaging-based diagnosisand timely standardized intervention, including intensive blood pressure and heart rate control, open surgical repair, and endovascular repair. Although substantial progress has been made in elucidating the mechanisms of PCD, clinical translational evidence for precision therapies targeting specific cell death pathways remains limited. Therefore, this review summarizes the mechanistic roles of PCD in AD and integrates these insights with emerging strategies for early diagnosis and precision treatment.
PMID:42720823 | DOI:10.1007/s11033-026-12538-8
Sci Adv. 2026 Sep 4;12(36):eaeg1640. doi: 10.1126/sciadv.aeg1640. Epub 2026 Sep 2.
ABSTRACT
Thoracic aortic aneurysms and dissections (TAAD) are life-threatening conditions linked to gain-of-function mutations in cGMP-dependent protein kinase I (PKG I), a central regulator of vascular smooth muscle signaling. Among these, substitutions at Val234 have been associated with kinase overactivation and early-onset disease, despite this residue being distal from the active site and cGMP binding regions. Using NMR, molecular dynamics simulations, and complementary kinase and binding assays, we show that Val234 acts as a crucial allosteric hub of PKG autoinhibition. TAAD-associated variants at Val234 disrupt PKG regulation through two distinct yet complementary allosteric mechanisms: by biasing the kinase toward active conformations that increase sensitivity to cGMP and by decreasing the folding stability of the regulatory domain, thereby weakening inhibitory contacts independently of cGMP control. Despite these differences, both mechanisms result in excessive PKG signaling at basal and intermediate cGMP levels, while maximal activity remains unaltered. Together, these findings explain how distal mutations can unpredictably rewire kinase allostery and drive pathogenic vascular signaling.
PMID:42685200 | PMC:PMC13537252 | DOI:10.1126/sciadv.aeg1640
Sci Adv. 2026 Sep 4;12(36):eaeg1640. doi: 10.1126/sciadv.aeg1640. Epub 2026 Sep 2.
ABSTRACT
Thoracic aortic aneurysms and dissections (TAAD) are life-threatening conditions linked to gain-of-function mutations in cGMP-dependent protein kinase I (PKG I), a central regulator of vascular smooth muscle signaling. Among these, substitutions at Val234 have been associated with kinase overactivation and early-onset disease, despite this residue being distal from the active site and cGMP binding regions. Using NMR, molecular dynamics simulations, and complementary kinase and binding assays, we show that Val234 acts as a crucial allosteric hub of PKG autoinhibition. TAAD-associated variants at Val234 disrupt PKG regulation through two distinct yet complementary allosteric mechanisms: by biasing the kinase toward active conformations that increase sensitivity to cGMP and by decreasing the folding stability of the regulatory domain, thereby weakening inhibitory contacts independently of cGMP control. Despite these differences, both mechanisms result in excessive PKG signaling at basal and intermediate cGMP levels, while maximal activity remains unaltered. Together, these findings explain how distal mutations can unpredictably rewire kinase allostery and drive pathogenic vascular signaling.
PMID:42685200 | PMC:PMC13537252 | DOI:10.1126/sciadv.aeg1640
Mol Biol Rep. 2026 Aug 27;53(1):1469. doi: 10.1007/s11033-026-12621-0.
ABSTRACT
tRNA-derived small RNAs (tsRNAs) are noncoding RNAs generated from precursor or mature tRNAs. Basal tsRNA levels are detectable under physiological conditions, but their production increases sharply under cellular stress. tsRNAs regulate gene expression through miRNA-like targeting, translational control, and intercellular communication. In vascular remodelling disorders-including atherosclerosis (AS), aortic dissection (AD), and in-stent restenosis (ISR)-vascular smooth muscle cells (VSMCs) undergo phenotypic switching from contractile to synthetic states. Pulmonary hypertension (PH) shares similar phenotypic features, but the current evidence on the role of tsRNAs in PH remains largely predictive. Several experimentally studied tsRNAs affect VSMC phenotypic behaviour in disease- and context-dependent manners by targeting key signalling molecules, including STAT4, FMOD, FAS, and CBX3/HP1\u03b3, with downstream consequences for contractile gene expression and proliferative behaviour. Notably, these tsRNAs act bidirectionally: 5'-tiRNA-Cys-GCA and tRF-Glu-CTC (via FMOD targeting) suppress the synthetic phenotype and neointimal formation, whereas tRF-Gln-CTG promotes it. We propose an evidence-mapped conceptual framework organized by regulatory layers-transcriptional, posttranscriptional, and chromatin-associated regulation-while acknowledging that cross-layer interactions remain to be experimentally verified. Clinically, tsRNAs hold promise as liquid biopsy biomarkers and therapeutic targets, but the current evidence is preliminary and requires validation against established biomarkers before translational application. This review synthesizes the current evidence on tsRNA biology in the context of VSMC phenotypic switching and outlines a roadmap for future research.
PMID:42658340 | DOI:10.1007/s11033-026-12621-0
Mol Biol Rep. 2026 Aug 27;53(1):1469. doi: 10.1007/s11033-026-12621-0.
ABSTRACT
tRNA-derived small RNAs (tsRNAs) are noncoding RNAs generated from precursor or mature tRNAs. Basal tsRNA levels are detectable under physiological conditions, but their production increases sharply under cellular stress. tsRNAs regulate gene expression through miRNA-like targeting, translational control, and intercellular communication. In vascular remodelling disorders-including atherosclerosis (AS), aortic dissection (AD), and in-stent restenosis (ISR)-vascular smooth muscle cells (VSMCs) undergo phenotypic switching from contractile to synthetic states. Pulmonary hypertension (PH) shares similar phenotypic features, but the current evidence on the role of tsRNAs in PH remains largely predictive. Several experimentally studied tsRNAs affect VSMC phenotypic behaviour in disease- and context-dependent manners by targeting key signalling molecules, including STAT4, FMOD, FAS, and CBX3/HP1\u03b3, with downstream consequences for contractile gene expression and proliferative behaviour. Notably, these tsRNAs act bidirectionally: 5'-tiRNA-Cys-GCA and tRF-Glu-CTC (via FMOD targeting) suppress the synthetic phenotype and neointimal formation, whereas tRF-Gln-CTG promotes it. We propose an evidence-mapped conceptual framework organized by regulatory layers-transcriptional, posttranscriptional, and chromatin-associated regulation-while acknowledging that cross-layer interactions remain to be experimentally verified. Clinically, tsRNAs hold promise as liquid biopsy biomarkers and therapeutic targets, but the current evidence is preliminary and requires validation against established biomarkers before translational application. This review synthesizes the current evidence on tsRNA biology in the context of VSMC phenotypic switching and outlines a roadmap for future research.
PMID:42658340 | DOI:10.1007/s11033-026-12621-0
Arterioscler Thromb Vasc Biol. 2026 Oct;46(10):e325325. doi: 10.1161/ATVBAHA.126.325325. Epub 2026 Aug 27.
NO ABSTRACT
PMID:42657468 | PMC:PMC13523102 | DOI:10.1161/ATVBAHA.126.325325
Arterioscler Thromb Vasc Biol. 2026 Oct;46(10):e325325. doi: 10.1161/ATVBAHA.126.325325. Epub 2026 Aug 27.
NO ABSTRACT
PMID:42657468 | PMC:PMC13523102 | DOI:10.1161/ATVBAHA.126.325325
Biomolecules. 2026 Jul 28;16(8):1101. doi: 10.3390/biom16081101.
ABSTRACT
Aortic dissection (AD) is a severe vascular condition marked by abrupt onset, rapid progression, and heightened mortality rates. Vascular smooth muscle cells (VSMCs), the predominant cellular component of the arterial media, are essential for maintaining the structural integrity and functionality of blood vessels. Recent studies have associated Cysteine-rich protein 2 (CSRP2) with the advancement of several vascular diseases. The involvement of CSRP2 in AD progression is unclear. Aortic tissues were collected from patients for RNA sequencing and histological analysis. A mouse model of AD was created using \u03b2-aminopropionitrile monofumarate (BAPN), while VSMC phenotypic switching was induced by platelet-derived growth factor BB (PDGF-BB). Adeno-associated virus vector was used to overexpress CSRP2 in aorta. A variety of histopathological assays and biochemical analyses were applied to determine gene and protein expression patterns as well as uncover underlying molecular mechanisms. CSRP2 was significantly downregulated in both human and murine AD, and CSRP2 gene overexpression dramatically reduced BAPN-induced AD incidence and prevented animal mortality. CSRP2 could preserve a contractile VSMC phenotype, even though under PDGF-BB stimulation. Mechanistically, our findings reveal that CSRP2 directly interacts with p130 Crk-associated substrate (p130Cas; also known as BCAR1) and reduces its phosphorylation, which in turn inhibits the activation of extracellular signal-regulated kinase (ERK) signaling pathways, thereby preventing VSMC phenotypic switching induced by PDGF-BB. Our findings identify CSRP2 as a novel regulator of VSMC phenotypic modulation and a significant modulator of AD development, suggesting its potential as a target for early intervention for AD.
PMID:42650769 | PMC:PMC13511068 | DOI:10.3390/biom16081101
Biomolecules. 2026 Jul 28;16(8):1101. doi: 10.3390/biom16081101.
ABSTRACT
Aortic dissection (AD) is a severe vascular condition marked by abrupt onset, rapid progression, and heightened mortality rates. Vascular smooth muscle cells (VSMCs), the predominant cellular component of the arterial media, are essential for maintaining the structural integrity and functionality of blood vessels. Recent studies have associated Cysteine-rich protein 2 (CSRP2) with the advancement of several vascular diseases. The involvement of CSRP2 in AD progression is unclear. Aortic tissues were collected from patients for RNA sequencing and histological analysis. A mouse model of AD was created using \u03b2-aminopropionitrile monofumarate (BAPN), while VSMC phenotypic switching was induced by platelet-derived growth factor BB (PDGF-BB). Adeno-associated virus vector was used to overexpress CSRP2 in aorta. A variety of histopathological assays and biochemical analyses were applied to determine gene and protein expression patterns as well as uncover underlying molecular mechanisms. CSRP2 was significantly downregulated in both human and murine AD, and CSRP2 gene overexpression dramatically reduced BAPN-induced AD incidence and prevented animal mortality. CSRP2 could preserve a contractile VSMC phenotype, even though under PDGF-BB stimulation. Mechanistically, our findings reveal that CSRP2 directly interacts with p130 Crk-associated substrate (p130Cas; also known as BCAR1) and reduces its phosphorylation, which in turn inhibits the activation of extracellular signal-regulated kinase (ERK) signaling pathways, thereby preventing VSMC phenotypic switching induced by PDGF-BB. Our findings identify CSRP2 as a novel regulator of VSMC phenotypic modulation and a significant modulator of AD development, suggesting its potential as a target for early intervention for AD.
PMID:42650769 | PMC:PMC13511068 | DOI:10.3390/biom16081101
Aging Med (Milton). 2026 Aug 24;9(4):416-425. doi: 10.1002/agm2.70106. eCollection 2026 Aug.
ABSTRACT
Aortic dissection (AD) is a life-threatening vascular disorder characterized by separation of the layers of the aortic wall, primarily triggered by an intimal tear or an intramural hemorrhage. Age is a well-recognized and critical risk factor for AD. Epidemiological evidence consistently demonstrates a strong positive correlation between age and AD incidence, with peak occurrence in the 50-70-year age group. Its pathogenesis involves vascular inflammation, extracellular matrix (ECM) degradation, vascular smooth muscle cell (VSMC) phenotypic switching, apoptosis, and immune cell infiltration. Two major pathophysiological theories have been proposed: one suggests a primary intimal tear, and the other involves medial degeneration from stress concentration. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides and account for ~80% of the human noncoding transcriptome. They exert diverse biological functions (e.g., miRNA sponging, protein scaffolding, transcriptional regulation) and are pivotal in diseases such as cancer, rheumatoid arthritis, and AD. Despite emerging evidence linking lncRNAs to AD, most studies to date have focused only on their role as competing endogenous RNAs (ceRNAs), with limited mechanistic depth and scarce clinical validation. This review summarizes the pathophysiology of AD and systematically discusses lncRNA-mediated mechanisms in AD progression. We highlight current knowledge gaps and propose future directions for exploring lncRNAs as potential therapeutic targets to improve AD prognosis.
PMID:42639312 | PMC:PMC13502957 | DOI:10.1002/agm2.70106
Aging Med (Milton). 2026 Aug 24;9(4):416-425. doi: 10.1002/agm2.70106. eCollection 2026 Aug.
ABSTRACT
Aortic dissection (AD) is a life-threatening vascular disorder characterized by separation of the layers of the aortic wall, primarily triggered by an intimal tear or an intramural hemorrhage. Age is a well-recognized and critical risk factor for AD. Epidemiological evidence consistently demonstrates a strong positive correlation between age and AD incidence, with peak occurrence in the 50-70-year age group. Its pathogenesis involves vascular inflammation, extracellular matrix (ECM) degradation, vascular smooth muscle cell (VSMC) phenotypic switching, apoptosis, and immune cell infiltration. Two major pathophysiological theories have been proposed: one suggests a primary intimal tear, and the other involves medial degeneration from stress concentration. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides and account for ~80% of the human noncoding transcriptome. They exert diverse biological functions (e.g., miRNA sponging, protein scaffolding, transcriptional regulation) and are pivotal in diseases such as cancer, rheumatoid arthritis, and AD. Despite emerging evidence linking lncRNAs to AD, most studies to date have focused only on their role as competing endogenous RNAs (ceRNAs), with limited mechanistic depth and scarce clinical validation. This review summarizes the pathophysiology of AD and systematically discusses lncRNA-mediated mechanisms in AD progression. We highlight current knowledge gaps and propose future directions for exploring lncRNAs as potential therapeutic targets to improve AD prognosis.
PMID:42639312 | PMC:PMC13502957 | DOI:10.1002/agm2.70106
Front Immunol. 2026 Aug 6;17:1878406. doi: 10.3389/fimmu.2026.1878406. eCollection 2026.
ABSTRACT
Aortic dissection (AD) has traditionally been viewed as an acute structural failure initiated by an intimal tear. However, accumulating evidence suggests that this catastrophic event represents the endpoint of a prolonged, multiscale process of vascular wall homeostatic imbalance. In this review, we propose an integrative framework in which AD arises from the progressive destabilization of a tightly coupled system involving endothelial function, vascular smooth muscle cell phenotype, extracellular matrix integrity, and vasa vasorum dynamics. Central to this model is the vascular-inflammation-metabolism axis, where microvascular dysfunction induces hypoxia, metabolic reprogramming, and oxidative stress, thereby triggering inflammatory amplification and matrix degradation. These processes interact through nonlinear feedback loops, gradually reducing the mechanical resilience of the aortic wall and driving it toward a critical transition. Importantly, the intimal tear is redefined not as the primary cause but as the final manifestation of underlying biological instability. This systems-level perspective reconciles clinical heterogeneity, including variable susceptibility, diverse disease trajectories, and cases lacking clear primary tears. By linking molecular, cellular, and biomechanical mechanisms into a unified framework, this model provides a foundation for identifying early biomarkers, refining risk stratification, and developing targeted therapeutic strategies aimed at restoring vascular homeostasis before catastrophic failure occurs.
PMID:42625977 | PMC:PMC13491038 | DOI:10.3389/fimmu.2026.1878406
Front Immunol. 2026 Aug 6;17:1878406. doi: 10.3389/fimmu.2026.1878406. eCollection 2026.
ABSTRACT
Aortic dissection (AD) has traditionally been viewed as an acute structural failure initiated by an intimal tear. However, accumulating evidence suggests that this catastrophic event represents the endpoint of a prolonged, multiscale process of vascular wall homeostatic imbalance. In this review, we propose an integrative framework in which AD arises from the progressive destabilization of a tightly coupled system involving endothelial function, vascular smooth muscle cell phenotype, extracellular matrix integrity, and vasa vasorum dynamics. Central to this model is the vascular-inflammation-metabolism axis, where microvascular dysfunction induces hypoxia, metabolic reprogramming, and oxidative stress, thereby triggering inflammatory amplification and matrix degradation. These processes interact through nonlinear feedback loops, gradually reducing the mechanical resilience of the aortic wall and driving it toward a critical transition. Importantly, the intimal tear is redefined not as the primary cause but as the final manifestation of underlying biological instability. This systems-level perspective reconciles clinical heterogeneity, including variable susceptibility, diverse disease trajectories, and cases lacking clear primary tears. By linking molecular, cellular, and biomechanical mechanisms into a unified framework, this model provides a foundation for identifying early biomarkers, refining risk stratification, and developing targeted therapeutic strategies aimed at restoring vascular homeostasis before catastrophic failure occurs.
PMID:42625977 | PMC:PMC13491038 | DOI:10.3389/fimmu.2026.1878406
Cardiovasc Drugs Ther. 2026 Oct;40(5):2115-2116. doi: 10.1007/s10557-026-07932-0. Epub 2026 Aug 11.
ABSTRACT
Wang et al. recently identified a novel post-translational mechanism in aortic dissection (AD) where DTX1 mediates ITGA5 ubiquitination to prevent vascular smooth muscle cell (VSMC) phenotypic switching. While their findings are robust, several mechanistic gaps remain. This letter expands on the functional implications of the ITGA5/ITGB1 heterodimer, proposes the involvement of deubiquitinases (DUBs) in rescuing ITGA5 from degradation, and explores the upstream epigenetic and inflammatory triggers of DTX1 downregulation. By integrating recent evidence on epigenetic modulators like SIRT1, we suggest that restoring upstream transcriptional regulators may offer more sustainable therapeutic outcomes than solely targeting downstream ITGA5 accumulation.
PMID:42579209 | DOI:10.1007/s10557-026-07932-0
Cardiovasc Drugs Ther. 2026 Oct;40(5):2115-2116. doi: 10.1007/s10557-026-07932-0. Epub 2026 Aug 11.
ABSTRACT
Wang et al. recently identified a novel post-translational mechanism in aortic dissection (AD) where DTX1 mediates ITGA5 ubiquitination to prevent vascular smooth muscle cell (VSMC) phenotypic switching. While their findings are robust, several mechanistic gaps remain. This letter expands on the functional implications of the ITGA5/ITGB1 heterodimer, proposes the involvement of deubiquitinases (DUBs) in rescuing ITGA5 from degradation, and explores the upstream epigenetic and inflammatory triggers of DTX1 downregulation. By integrating recent evidence on epigenetic modulators like SIRT1, we suggest that restoring upstream transcriptional regulators may offer more sustainable therapeutic outcomes than solely targeting downstream ITGA5 accumulation.
PMID:42579209 | DOI:10.1007/s10557-026-07932-0
J Adv Res. 2026 Aug 1:S2090-1232(26)00602-8. doi: 10.1016/j.jare.2026.07.057. Online ahead of print.
ABSTRACT
BACKGROUND: Aortic aneurysm (AA) and aortic dissection (AD) are catastrophic aortic disorders characterized by progressive structural weakening or acute medial tearing, often resulting in rupture and high mortality. Their complex and heterogeneous pathogenesis-spanning extracellular matrix degradation, vascular smooth muscle cell dysfunction, inflammation, and dysregulated signaling-necessitates robust experimental systems. Diverse animal and engineered models have been developed to capture key features of these diseases, yet each recapitulates only specific aspects of human pathology.
AIM OF REVIEW: This review aims to: (1) systematically summarize current experimental models of AA and AD, including chemical, genetic, and combined systems; (2) provide a decision tree for selecting mouse models of AA and AD for vascular research; (3) evaluate model-specific strengths, limitations, and translational relevance, while highlighting emerging technologies such as vascular organoids and engineered 3D platforms that may bridge gaps between preclinical research and human disease.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review presents an integrated framework linking aortic pathology to model-specific mechanisms, illustrating how extracellular matrix (ECM) failure, smooth muscle cell remodeling, inflammation, and biomechanical stress drive AA and AD. We further emphasize the translational hierarchy across mouse, large-animal, and organoid models, providing guidance for rational model selection in therapeutic discovery. By systematically summarizing classical and emerging mouse models of AA and AD, this review provides a structured framework to guide model selection and future mechanistic studies in the field.
PMID:42542243 | DOI:10.1016/j.jare.2026.07.057
J Adv Res. 2026 Aug 1:S2090-1232(26)00602-8. doi: 10.1016/j.jare.2026.07.057. Online ahead of print.
ABSTRACT
BACKGROUND: Aortic aneurysm (AA) and aortic dissection (AD) are catastrophic aortic disorders characterized by progressive structural weakening or acute medial tearing, often resulting in rupture and high mortality. Their complex and heterogeneous pathogenesis-spanning extracellular matrix degradation, vascular smooth muscle cell dysfunction, inflammation, and dysregulated signaling-necessitates robust experimental systems. Diverse animal and engineered models have been developed to capture key features of these diseases, yet each recapitulates only specific aspects of human pathology.
AIM OF REVIEW: This review aims to: (1) systematically summarize current experimental models of AA and AD, including chemical, genetic, and combined systems; (2) provide a decision tree for selecting mouse models of AA and AD for vascular research; (3) evaluate model-specific strengths, limitations, and translational relevance, while highlighting emerging technologies such as vascular organoids and engineered 3D platforms that may bridge gaps between preclinical research and human disease.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review presents an integrated framework linking aortic pathology to model-specific mechanisms, illustrating how extracellular matrix (ECM) failure, smooth muscle cell remodeling, inflammation, and biomechanical stress drive AA and AD. We further emphasize the translational hierarchy across mouse, large-animal, and organoid models, providing guidance for rational model selection in therapeutic discovery. By systematically summarizing classical and emerging mouse models of AA and AD, this review provides a structured framework to guide model selection and future mechanistic studies in the field.
PMID:42542243 | DOI:10.1016/j.jare.2026.07.057
Sheng Wu Gong Cheng Xue Bao. 2026 Jul 25;42(7):2927-2942. doi: 10.13345/j.cjb.260197.
ABSTRACT
Aortic aneurysms, including thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA), represent a group of severe vascular lesions with insidious onset and high mortality. Currently, effective diagnostic markers and pharmacological interventions remain lacking in clinical practice. Extracellular vesicles (EVs), as key mediators of intercellular communication, have attracted increasing attention in the research on aortic aneurysms due to their high content of bioactive molecules, favorable biocompatibility, low immunogenicity, and inherent targeting capacity. This review systematically elaborated on the research progress on EVs in TAA and AAA, highlighting their significant role in the development and progression of aortic aneurysms. EVs play a crucial role by mediating core pathological processes, including endothelial dysfunction, phenotypic transformation of vascular smooth muscle cells, inflammatory immune responses, and extracellular matrix remodeling. Additionally, this review discussed the potential of disease-specific molecules carried by EVs as novel liquid biopsy markers for the early diagnosis of aortic aneurysms. Furthermore, this review evaluated the application prospects of EVs as natural drug delivery platforms and EV-based therapeutic strategies for aortic aneurysm through engineering modifications (such as targeting peptide modification and biomaterial integration). In particular, \"cell-free\" immunomodulatory therapies, which enhance targeting capacity to lesion sites through engineering modifications and focus strategically on regulating the phenotype and function of key immune cells (such as macrophages), are increasingly emerging as a cutting-edge direction with the greatest translational potential in this field. Despite challenges such as targeted delivery, the integration of engineering technologies with nanomedicine holds promise for opening new avenues for the precise prevention and treatment of aortic aneurysms through EV-based integrated diagnostic and therapeutic strategies.
PMID:42522609 | DOI:10.13345/j.cjb.260197
Sheng Wu Gong Cheng Xue Bao. 2026 Jul 25;42(7):2927-2942. doi: 10.13345/j.cjb.260197.
ABSTRACT
Aortic aneurysms, including thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA), represent a group of severe vascular lesions with insidious onset and high mortality. Currently, effective diagnostic markers and pharmacological interventions remain lacking in clinical practice. Extracellular vesicles (EVs), as key mediators of intercellular communication, have attracted increasing attention in the research on aortic aneurysms due to their high content of bioactive molecules, favorable biocompatibility, low immunogenicity, and inherent targeting capacity. This review systematically elaborated on the research progress on EVs in TAA and AAA, highlighting their significant role in the development and progression of aortic aneurysms. EVs play a crucial role by mediating core pathological processes, including endothelial dysfunction, phenotypic transformation of vascular smooth muscle cells, inflammatory immune responses, and extracellular matrix remodeling. Additionally, this review discussed the potential of disease-specific molecules carried by EVs as novel liquid biopsy markers for the early diagnosis of aortic aneurysms. Furthermore, this review evaluated the application prospects of EVs as natural drug delivery platforms and EV-based therapeutic strategies for aortic aneurysm through engineering modifications (such as targeting peptide modification and biomaterial integration). In particular, \"cell-free\" immunomodulatory therapies, which enhance targeting capacity to lesion sites through engineering modifications and focus strategically on regulating the phenotype and function of key immune cells (such as macrophages), are increasingly emerging as a cutting-edge direction with the greatest translational potential in this field. Despite challenges such as targeted delivery, the integration of engineering technologies with nanomedicine holds promise for opening new avenues for the precise prevention and treatment of aortic aneurysms through EV-based integrated diagnostic and therapeutic strategies.
PMID:42522609 | DOI:10.13345/j.cjb.260197
J Clin Med. 2026 Jul 8;15(14):5342. doi: 10.3390/jcm15145342.
ABSTRACT
Background: Heritable thoracic aortic disease (HTAD) encompass a heterogeneous spectrum of conditions characterized by increased susceptibility to developing thoracic aortic aneurysm and life-threatening complications, including aortic dissection and rupture. Despite distinct underlying mechanisms involving extracellular matrix integrity, vascular smooth muscle cell function, and dysregulation of signaling pathways, these disorders converge on a shared vulnerability of the aortic wall. Although acute events typically occur in adulthood, the disease process often begins early in life, making HTAD highly relevant in pediatric practice, where early recognition and longitudinal management are essential. Aims: This narrative review provides a biology- and genetics-oriented, translational complement to current consensus recommendations, framing pediatric HTAD as a developmentally shaped disorder of the aortic wall in which genotype increasingly informs diagnosis, surveillance, and treatment. Methods: Relevant studies were identified through a comprehensive PubMed search, with particular focus on pathogenic mechanisms, current clinical guidelines, follow-up strategies and emerging genetic perspectives. Results: Genetic testing is emerging as a key tool for the management of HTAD, although its clinical utility remains limited by provisional genotype-phenotype correlations and inconclusive results. Current risk stratification is still mainly based on aortic diameter surveillance, while pharmacological strategies are predominantly extrapolated from Marfan syndrome trials, highlighting important gaps in evidence. Conclusions: Genetic advances are expanding management opportunities in HTAD, but their clinical translation remains challenging. Disease-specific risk models integrating genetic and clinical data may improve individualized risk stratification, treatment strategies and clinical outcomes.
PMID:42513256 | PMC:PMC13411444 | DOI:10.3390/jcm15145342
J Clin Med. 2026 Jul 8;15(14):5342. doi: 10.3390/jcm15145342.
ABSTRACT
Background: Heritable thoracic aortic disease (HTAD) encompass a heterogeneous spectrum of conditions characterized by increased susceptibility to developing thoracic aortic aneurysm and life-threatening complications, including aortic dissection and rupture. Despite distinct underlying mechanisms involving extracellular matrix integrity, vascular smooth muscle cell function, and dysregulation of signaling pathways, these disorders converge on a shared vulnerability of the aortic wall. Although acute events typically occur in adulthood, the disease process often begins early in life, making HTAD highly relevant in pediatric practice, where early recognition and longitudinal management are essential. Aims: This narrative review provides a biology- and genetics-oriented, translational complement to current consensus recommendations, framing pediatric HTAD as a developmentally shaped disorder of the aortic wall in which genotype increasingly informs diagnosis, surveillance, and treatment. Methods: Relevant studies were identified through a comprehensive PubMed search, with particular focus on pathogenic mechanisms, current clinical guidelines, follow-up strategies and emerging genetic perspectives. Results: Genetic testing is emerging as a key tool for the management of HTAD, although its clinical utility remains limited by provisional genotype-phenotype correlations and inconclusive results. Current risk stratification is still mainly based on aortic diameter surveillance, while pharmacological strategies are predominantly extrapolated from Marfan syndrome trials, highlighting important gaps in evidence. Conclusions: Genetic advances are expanding management opportunities in HTAD, but their clinical translation remains challenging. Disease-specific risk models integrating genetic and clinical data may improve individualized risk stratification, treatment strategies and clinical outcomes.
PMID:42513256 | PMC:PMC13411444 | DOI:10.3390/jcm15145342
Genes (Basel). 2026 Jun 30;17(7):770. doi: 10.3390/genes17070770.
ABSTRACT
Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-\u03b2, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type-specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies.
PMID:42510811 | PMC:PMC13409517 | DOI:10.3390/genes17070770
Genes (Basel). 2026 Jun 30;17(7):770. doi: 10.3390/genes17070770.
ABSTRACT
Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-\u03b2, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type-specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies.
PMID:42510811 | PMC:PMC13409517 | DOI:10.3390/genes17070770
Antioxidants (Basel). 2026 Jun 30;15(7):831. doi: 10.3390/antiox15070831.
ABSTRACT
Aortic dissection (AD) is a life-threatening vascular disease characterized by progressive vascular remodeling, oxidative stress, and inflammation. Among them, severe oxidative stress and systemic inflammation are important driving factors causing vascular integrity damage. Cistanche deserticola polysaccharides (CTPs) have definite deserticola anti-inflammatory and antioxidant properties. However, their influence on the progression of AD remains to be studied. In this study, we investigated the protective effects of CTP in a BAPN-induced mouse model of aortic dissection and explored the underlying mechanisms. CTP administration significantly attenuated aortic dilation and reduced the incidence of aortic dissection, accompanied by suppression of oxidative stress and inflammatory responses, preservation of extracellular matrix integrity, and maintenance of the contractile phenotype of vascular smooth muscle cells. Most importantly, CTP inhibits oxidative stress responses, as evidenced by the recovery of endogenous antioxidant enzyme activity and the reduction in lipid peroxidation. At the same time, CTP also suppresses systemic inflammatory responses. In addition, CTP markedly reshaped gut microbiota composition, characterized by enrichment of Akkermansia and Lachnospiraceae and reduction in Desulfovibrio and Escherichia-Shigella. Correlation analyses revealed close associations between gut microbial alterations and antioxidant, vascular remodeling, and smooth muscle cell phenotypic modulation. Collectively, these findings suggest that CTP confers vascular protection against aortic dissection through coordinated regulation of oxidative stress, inflammation, and vascular remodeling. The observed changes in gut microbiota composition may represent an additional mechanism associated with the beneficial effects of CTP and warrant further investigation.
PMID:42510562 | PMC:PMC13404642 | DOI:10.3390/antiox15070831
Antioxidants (Basel). 2026 Jun 30;15(7):831. doi: 10.3390/antiox15070831.
ABSTRACT
Aortic dissection (AD) is a life-threatening vascular disease characterized by progressive vascular remodeling, oxidative stress, and inflammation. Among them, severe oxidative stress and systemic inflammation are important driving factors causing vascular integrity damage. Cistanche deserticola polysaccharides (CTPs) have definite deserticola anti-inflammatory and antioxidant properties. However, their influence on the progression of AD remains to be studied. In this study, we investigated the protective effects of CTP in a BAPN-induced mouse model of aortic dissection and explored the underlying mechanisms. CTP administration significantly attenuated aortic dilation and reduced the incidence of aortic dissection, accompanied by suppression of oxidative stress and inflammatory responses, preservation of extracellular matrix integrity, and maintenance of the contractile phenotype of vascular smooth muscle cells. Most importantly, CTP inhibits oxidative stress responses, as evidenced by the recovery of endogenous antioxidant enzyme activity and the reduction in lipid peroxidation. At the same time, CTP also suppresses systemic inflammatory responses. In addition, CTP markedly reshaped gut microbiota composition, characterized by enrichment of Akkermansia and Lachnospiraceae and reduction in Desulfovibrio and Escherichia-Shigella. Correlation analyses revealed close associations between gut microbial alterations and antioxidant, vascular remodeling, and smooth muscle cell phenotypic modulation. Collectively, these findings suggest that CTP confers vascular protection against aortic dissection through coordinated regulation of oxidative stress, inflammation, and vascular remodeling. The observed changes in gut microbiota composition may represent an additional mechanism associated with the beneficial effects of CTP and warrant further investigation.
PMID:42510562 | PMC:PMC13404642 | DOI:10.3390/antiox15070831
Biochem Pharmacol. 2026 Nov;253(Pt 1):118294. doi: 10.1016/j.bcp.2026.118294. Epub 2026 Jul 27.
ABSTRACT
Aortic aneurysm and dissection (AAD) are life-threatening vascular diseases for which effective pharmacological therapies remain limited. Smooth muscle cell phenotypic switching plays a central role in AAD development and progression. Orforglipron, a novel orally active non-peptide glucagon-like peptide-1 receptor agonist, has shown potential cardiovascular benefits; however, its role in AAD remains unclear. In this study, male B6 humanized GLP-1R mice were treated with orforglipron by oral gavage for 28 consecutive days and subjected to beta-aminopropionitrile combined with angiotensin II infusion to induce AAD. Orforglipron treatment protected mice from smooth muscle cell phenotypic switching, medial degeneration, and AAD formation. RNA sequencing of human aortic smooth muscle cells identified Wnt5a as a key downstream target regulated by orforglipron. Mechanistically, orforglipron inhibited ERK phosphorylation, reduced EGR1 expression, and thereby suppressed EGR1-mediated Wnt5a transcription. Conditional deletion of Wnt5a in smooth muscle cells significantly attenuated AAD progression, whereas activation of JNK signaling aggravated vascular remodeling and AAD development. These findings demonstrate that orforglipron attenuates smooth muscle cell phenotypic switching and AAD progression by modulating the ERK/EGR1/Wnt5a/JNK signaling axis, supporting orforglipron as a promising therapeutic candidate for aortic diseases.
PMID:42508653 | DOI:10.1016/j.bcp.2026.118294
Biochem Pharmacol. 2026 Nov;253(Pt 1):118294. doi: 10.1016/j.bcp.2026.118294. Epub 2026 Jul 27.
ABSTRACT
Aortic aneurysm and dissection (AAD) are life-threatening vascular diseases for which effective pharmacological therapies remain limited. Smooth muscle cell phenotypic switching plays a central role in AAD development and progression. Orforglipron, a novel orally active non-peptide glucagon-like peptide-1 receptor agonist, has shown potential cardiovascular benefits; however, its role in AAD remains unclear. In this study, male B6 humanized GLP-1R mice were treated with orforglipron by oral gavage for 28 consecutive days and subjected to beta-aminopropionitrile combined with angiotensin II infusion to induce AAD. Orforglipron treatment protected mice from smooth muscle cell phenotypic switching, medial degeneration, and AAD formation. RNA sequencing of human aortic smooth muscle cells identified Wnt5a as a key downstream target regulated by orforglipron. Mechanistically, orforglipron inhibited ERK phosphorylation, reduced EGR1 expression, and thereby suppressed EGR1-mediated Wnt5a transcription. Conditional deletion of Wnt5a in smooth muscle cells significantly attenuated AAD progression, whereas activation of JNK signaling aggravated vascular remodeling and AAD development. These findings demonstrate that orforglipron attenuates smooth muscle cell phenotypic switching and AAD progression by modulating the ERK/EGR1/Wnt5a/JNK signaling axis, supporting orforglipron as a promising therapeutic candidate for aortic diseases.
PMID:42508653 | DOI:10.1016/j.bcp.2026.118294
Front Cardiovasc Med. 2026 Jul 10;13:1831795. doi: 10.3389/fcvm.2026.1831795. eCollection 2026.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disease. ARHGAP27 can regulate cytoskeleton and cellular functions, which may be related to the phenotypic switching of vascular smooth muscle cells (VSMCs) in AD. However, the role of ARHGAP27 in AD has not been reported yet.
METHODS: The AD-related data sets were downloaded from GEO database to screen differential genes. HE and IHC staining was used to detect the pathological changes and the expression level of ARHGAP27 in AD tissue. AD cell models were constructed in vitro by inducing HAVSMCs with PDGF-BB to evaluate the effects of ARHGAP27 overexpression or knockdown on cell survival, migration, invasion and phenotypic switching. Rescue experiments were performed using the ROCK activator LPA to test pathway specificity.
RESULTS: ARHGAP27 was significantly upregulated in the dataset and the tissue. In vitro experiments have shown that overexpression of ARHGAP27 can further promote the survival, migration and invasion of VSMCs, and the expression of synthetic phenotypic proteins MMP2 and MMP9, and inhibit the expression of contraction phenotypes \u03b1-SMA and SM22\u03b1. Knockdown of ARHGAP27-2 can obtain the opposite result. In terms of mechanism, PDGF-BB down-regulates the expression levels of RhoA, ROCK1/2, and up-regulates the phosphorylation levels of YAP in VSMCs. Overexpression of ARHGAP27 further enhances the effect of PDGF-BB, while knockdown of ARHGAP27-1 and ARHGAP27-2 inhibits the effect of PDGF-BB. Treatment with LPA would reverse the effects produced by ARHGAP27 overexpression.
CONCLUSION: ARHGAP27 is upregulated in AD and accelerates its pathological progression by regulating the RhoA/ROCK/YAP pathway.
PMID:42499796 | PMC:PMC13396006 | DOI:10.3389/fcvm.2026.1831795
Front Cardiovasc Med. 2026 Jul 10;13:1831795. doi: 10.3389/fcvm.2026.1831795. eCollection 2026.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disease. ARHGAP27 can regulate cytoskeleton and cellular functions, which may be related to the phenotypic switching of vascular smooth muscle cells (VSMCs) in AD. However, the role of ARHGAP27 in AD has not been reported yet.
METHODS: The AD-related data sets were downloaded from GEO database to screen differential genes. HE and IHC staining was used to detect the pathological changes and the expression level of ARHGAP27 in AD tissue. AD cell models were constructed in vitro by inducing HAVSMCs with PDGF-BB to evaluate the effects of ARHGAP27 overexpression or knockdown on cell survival, migration, invasion and phenotypic switching. Rescue experiments were performed using the ROCK activator LPA to test pathway specificity.
RESULTS: ARHGAP27 was significantly upregulated in the dataset and the tissue. In vitro experiments have shown that overexpression of ARHGAP27 can further promote the survival, migration and invasion of VSMCs, and the expression of synthetic phenotypic proteins MMP2 and MMP9, and inhibit the expression of contraction phenotypes \u03b1-SMA and SM22\u03b1. Knockdown of ARHGAP27-2 can obtain the opposite result. In terms of mechanism, PDGF-BB down-regulates the expression levels of RhoA, ROCK1/2, and up-regulates the phosphorylation levels of YAP in VSMCs. Overexpression of ARHGAP27 further enhances the effect of PDGF-BB, while knockdown of ARHGAP27-1 and ARHGAP27-2 inhibits the effect of PDGF-BB. Treatment with LPA would reverse the effects produced by ARHGAP27 overexpression.
CONCLUSION: ARHGAP27 is upregulated in AD and accelerates its pathological progression by regulating the RhoA/ROCK/YAP pathway.
PMID:42499796 | PMC:PMC13396006 | DOI:10.3389/fcvm.2026.1831795
JACC Case Rep. 2026 Sep 9;31(36):109444. doi: 10.1016/j.jaccas.2026.109444. Epub 2026 Jul 23.
ABSTRACT
BACKGROUND: Myosin light chain kinase (MYLK) variants of uncertain significance (VUS) are not considered actionable under current guidelines, yet MYLK encodes a kinase essential for vascular smooth muscle contractility, and pathogenic variants are associated with aortic dissection at modest diameters.
CASE SUMMARY: We report 8 patients carrying MYLK variants (7 VUS, 1 pathogenic) who developed aortic dissection requiring surgery. In our institutional registry of 1,048 patients undergoing aortic genetic panel testing, MYLK carriers had higher rates of acute aortic syndromes, namely Type A dissections.
DISCUSSION: Four phenotypic patterns emerged: dissection at aortic diameters of 40 mm (below guideline thresholds); reoperation at a median of 7 vs 24 months in non-MYLK dissection patients; co-occurring ACTA2 VUS suggesting oligogenic risk amplification; and intrapedigree VUS-to-pathogenic reclassification of the same MYLK V1522A variant across 2 timepoints and testing facilities.
CONCLUSIONS: The MYLK variant patient journeys support lower surveillance thresholds and cascade genetic screening.
PMID:42489613 | PMC:PMC13571357 | DOI:10.1016/j.jaccas.2026.109444
JACC Case Rep. 2026 Sep 9;31(36):109444. doi: 10.1016/j.jaccas.2026.109444. Epub 2026 Jul 23.
ABSTRACT
BACKGROUND: Myosin light chain kinase (MYLK) variants of uncertain significance (VUS) are not considered actionable under current guidelines, yet MYLK encodes a kinase essential for vascular smooth muscle contractility, and pathogenic variants are associated with aortic dissection at modest diameters.
CASE SUMMARY: We report 8 patients carrying MYLK variants (7 VUS, 1 pathogenic) who developed aortic dissection requiring surgery. In our institutional registry of 1,048 patients undergoing aortic genetic panel testing, MYLK carriers had higher rates of acute aortic syndromes, namely Type A dissections.
DISCUSSION: Four phenotypic patterns emerged: dissection at aortic diameters of 40 mm (below guideline thresholds); reoperation at a median of 7 vs 24 months in non-MYLK dissection patients; co-occurring ACTA2 VUS suggesting oligogenic risk amplification; and intrapedigree VUS-to-pathogenic reclassification of the same MYLK V1522A variant across 2 timepoints and testing facilities.
CONCLUSIONS: The MYLK variant patient journeys support lower surveillance thresholds and cascade genetic screening.
PMID:42489613 | PMC:PMC13571357 | DOI:10.1016/j.jaccas.2026.109444
Arterioscler Thromb Vasc Biol. 2026 Oct;46(10):e324930. doi: 10.1161/ATVBAHA.126.324930. Epub 2026 Jul 23.
ABSTRACT
BACKGROUND: Aortic aneurysm and dissection (AAD) is a life-threatening vascular disease that currently lacks effective pharmacological therapies. Clinical evidences suggest that aspirin may exert a protective effect on AAD, but the underlying molecular mechanism is still unclear at present.
METHODS: Three mouse animal models of AAD and H2O2-induced ferroptosis model in human aortic vascular smooth muscle cells (HAVSMCs) were established. On this basis, RNA sequencing was performed to investigate potential molecular mechanisms, and further experiments were conducted using STING (stimulator of interferon genes) agonist to confirm the mechanisms.
RESULTS: Aspirin was found to ameliorate the progression of AAD in the \u03b2-aminopropionitrile and CaPO4 mouse models. Interestingly, aspirin reduced mortality in mice but did not reduce the incidence of AAD in the \u03b2-aminopropionitrile + angiotensin II model. Furthermore, aspirin inhibited H2O2-induced ferroptosis in HAVSMCs and suppressed activation of cGAS (cyclic GMP-AMP synthase)-STING signaling pathway. Activation of STING with STING agonist markedly increased STING, TBK1 (TANK-binding kinase 1), and IRF3 (interferon regulatory factor 3) phosphorylation and abolished the protective effect of aspirin against H2O2-induced ferroptosis in HAVSMCs. Western blot and immunofluorescence results indicated significant activation of the cGAS-STING signaling pathway following treatment with STING agonist. Coimmunoprecipitation analysis revealed that cGAS acetylation was considerably enhanced in HAVSMCs after aspirin treatment. Additionally, administration of aspirin and dimeric amidobenzimidazole compound 3 showed that dimeric amidobenzimidazole abolished the protective effect of aspirin in the CaPO4 model. Coimmunoprecipitation results indicated that aspirin promoted cGAS acetylation in mouse aortic tissue. Western blot and immunohistochemistry results also confirmed that the dimeric amidobenzimidazole compound 3 activated phosphorylation of STING, TBK1, and IRF3 and significantly negatively regulated the expression of GPX4 (glutathione peroxidase). In the \u03b2-aminopropionitrile model, dimeric amidobenzimidazole also abolished the protective effect of aspirin.
CONCLUSIONS: Aspirin confers a protective effect against AAD by promoting cGAS acetylation and inhibiting the cGAS-STING signaling pathway and ferroptosis in VSMC.
PMID:42488945 | DOI:10.1161/ATVBAHA.126.324930
Arterioscler Thromb Vasc Biol. 2026 Oct;46(10):e324930. doi: 10.1161/ATVBAHA.126.324930. Epub 2026 Jul 23.
ABSTRACT
BACKGROUND: Aortic aneurysm and dissection (AAD) is a life-threatening vascular disease that currently lacks effective pharmacological therapies. Clinical evidences suggest that aspirin may exert a protective effect on AAD, but the underlying molecular mechanism is still unclear at present.
METHODS: Three mouse animal models of AAD and H2O2-induced ferroptosis model in human aortic vascular smooth muscle cells (HAVSMCs) were established. On this basis, RNA sequencing was performed to investigate potential molecular mechanisms, and further experiments were conducted using STING (stimulator of interferon genes) agonist to confirm the mechanisms.
RESULTS: Aspirin was found to ameliorate the progression of AAD in the \u03b2-aminopropionitrile and CaPO4 mouse models. Interestingly, aspirin reduced mortality in mice but did not reduce the incidence of AAD in the \u03b2-aminopropionitrile + angiotensin II model. Furthermore, aspirin inhibited H2O2-induced ferroptosis in HAVSMCs and suppressed activation of cGAS (cyclic GMP-AMP synthase)-STING signaling pathway. Activation of STING with STING agonist markedly increased STING, TBK1 (TANK-binding kinase 1), and IRF3 (interferon regulatory factor 3) phosphorylation and abolished the protective effect of aspirin against H2O2-induced ferroptosis in HAVSMCs. Western blot and immunofluorescence results indicated significant activation of the cGAS-STING signaling pathway following treatment with STING agonist. Coimmunoprecipitation analysis revealed that cGAS acetylation was considerably enhanced in HAVSMCs after aspirin treatment. Additionally, administration of aspirin and dimeric amidobenzimidazole compound 3 showed that dimeric amidobenzimidazole abolished the protective effect of aspirin in the CaPO4 model. Coimmunoprecipitation results indicated that aspirin promoted cGAS acetylation in mouse aortic tissue. Western blot and immunohistochemistry results also confirmed that the dimeric amidobenzimidazole compound 3 activated phosphorylation of STING, TBK1, and IRF3 and significantly negatively regulated the expression of GPX4 (glutathione peroxidase). In the \u03b2-aminopropionitrile model, dimeric amidobenzimidazole also abolished the protective effect of aspirin.
CONCLUSIONS: Aspirin confers a protective effect against AAD by promoting cGAS acetylation and inhibiting the cGAS-STING signaling pathway and ferroptosis in VSMC.
PMID:42488945 | DOI:10.1161/ATVBAHA.126.324930
Ageing Res Rev. 2026 Oct;121:103268. doi: 10.1016/j.arr.2026.103268. Epub 2026 Jul 20.
ABSTRACT
Cytoskeleton is an important component of cell structure and function. In the cardiovascular system, it is involved in the remodeling process of a variety of cardiovascular diseases, including cardiac fibrosis, valvular disease, atrial fibrillation, thoracic aortic aneurysm and vascular stiffness related changes. Recent studies have shown that there is a significant synergy between cytoskeletal regulation and epigenetic processes. Notably, epigenetic alterations have been identified as one of the core features of ageing, a major risk factor for cardiovascular disease. Together, these factors regulate the fate determination, function maintenance and pathological transformation of cardiovascular cells. This review focuses on how age-related epigenetic changes, such as DNA methylation, histone modifications, and chromatin remodeling, directly affect cytoskeletal dynamics and nuclear mechanics, and ultimately lead to cardiovascular remodeling. This review systematically summarizes the key molecular pathways that drive pathological remodeling of cardiomyocytes during contraction, phenotypic switching of vascular smooth muscle cells, and activation of fibroblasts. In addition, we discuss potential therapeutic targets, biomarkers, and intervention strategies in this rapidly evolving field to address current challenges and identify future directions for research in order to lay the theoretical foundation for precision medicine in cardiovascular disease.
PMID:42476320 | DOI:10.1016/j.arr.2026.103268
Ageing Res Rev. 2026 Oct;121:103268. doi: 10.1016/j.arr.2026.103268. Epub 2026 Jul 20.
ABSTRACT
Cytoskeleton is an important component of cell structure and function. In the cardiovascular system, it is involved in the remodeling process of a variety of cardiovascular diseases, including cardiac fibrosis, valvular disease, atrial fibrillation, thoracic aortic aneurysm and vascular stiffness related changes. Recent studies have shown that there is a significant synergy between cytoskeletal regulation and epigenetic processes. Notably, epigenetic alterations have been identified as one of the core features of ageing, a major risk factor for cardiovascular disease. Together, these factors regulate the fate determination, function maintenance and pathological transformation of cardiovascular cells. This review focuses on how age-related epigenetic changes, such as DNA methylation, histone modifications, and chromatin remodeling, directly affect cytoskeletal dynamics and nuclear mechanics, and ultimately lead to cardiovascular remodeling. This review systematically summarizes the key molecular pathways that drive pathological remodeling of cardiomyocytes during contraction, phenotypic switching of vascular smooth muscle cells, and activation of fibroblasts. In addition, we discuss potential therapeutic targets, biomarkers, and intervention strategies in this rapidly evolving field to address current challenges and identify future directions for research in order to lay the theoretical foundation for precision medicine in cardiovascular disease.
PMID:42476320 | DOI:10.1016/j.arr.2026.103268
Rev Cardiovasc Med. 2026 Jun 24;27(6):45868. doi: 10.31083/RCM45868. eCollection 2026 Jun.
ABSTRACT
Aortic aneurysm (AA) and aortic dissection (AD) are life-threatening aortic diseases that primarily arise from medial degeneration. Ruptures are invariably associated with fatal outcomes; however, there are currently no clinically proven medications to prevent the progression of aortic aneurysm and dissection (AAD), and surgery remains the most effective approach to eliminating the high risk of aortic rupture. The dysfunction and depletion of vascular smooth muscle cells, along with inflammation and extracellular matrix (ECM) remodeling, are key mechanisms underlying AAD development. Integrins are heterodimeric transmembrane receptors that link the ECM to the cytoskeleton and transmit bidirectional cellular signals. Moreover, integrins maintain cell morphology and modulate numerous physiological and pathophysiological processes. Meanwhile, increasing evidence indicates that integrins play a vital role in AAD. This review outlines the basic biology of integrins, discusses the specific functions and mechanisms of integrins in AAD pathogenesis, and aims to identify reliable non-invasive biomarkers for acute AAD and potential targets to halt disease progression.
PMID:42416583 | PMC:PMC13339237 | DOI:10.31083/RCM45868
Rev Cardiovasc Med. 2026 Jun 24;27(6):45868. doi: 10.31083/RCM45868. eCollection 2026 Jun.
ABSTRACT
Aortic aneurysm (AA) and aortic dissection (AD) are life-threatening aortic diseases that primarily arise from medial degeneration. Ruptures are invariably associated with fatal outcomes; however, there are currently no clinically proven medications to prevent the progression of aortic aneurysm and dissection (AAD), and surgery remains the most effective approach to eliminating the high risk of aortic rupture. The dysfunction and depletion of vascular smooth muscle cells, along with inflammation and extracellular matrix (ECM) remodeling, are key mechanisms underlying AAD development. Integrins are heterodimeric transmembrane receptors that link the ECM to the cytoskeleton and transmit bidirectional cellular signals. Moreover, integrins maintain cell morphology and modulate numerous physiological and pathophysiological processes. Meanwhile, increasing evidence indicates that integrins play a vital role in AAD. This review outlines the basic biology of integrins, discusses the specific functions and mechanisms of integrins in AAD pathogenesis, and aims to identify reliable non-invasive biomarkers for acute AAD and potential targets to halt disease progression.
PMID:42416583 | PMC:PMC13339237 | DOI:10.31083/RCM45868
Bioact Mater. 2026 Jun 24;65:984-1004. doi: 10.1016/j.bioactmat.2026.05.057. eCollection 2026 Nov.
ABSTRACT
Aortic dissection (AD) is a life-threatening cardiovascular emergency characterized by acute aortic wall injury and high mortality, yet effective pharmacological therapies remain limited. Macrophage infiltration and vascular smooth muscle cell (VSMC) phenotypic switching from contractile to synthetic states are central to AD pathogenesis, but the mechanisms mediating intercellular communication between macrophages and VSMCs are incompletely understood. Emerging evidence suggests that exosomes can transfer bioactive miRNAs between cells; however, whether M1 macrophage-derived exosomes promote AD progression through specific miRNA delivery and whether they can be engineered for therapeutic intervention have not been clearly defined. In this study, we demonstrate that M1 macrophage-derived exosomes deliver miR-155-5p to VSMCs, where it targets and suppresses SMAD5, activates the RHOA/ROCK pathway, and drives contractile-to-synthetic phenotypic switching, thereby accelerating AD progression. Through comprehensive physicochemical characterization, including TEM, NTA, Zeta potential, and stability assays, we show that M0 macrophage-derived exosomes can be successfully engineered to load Antago-miR-155-5p via electroporation with favorable encapsulation efficiency and colloidal stability. In a BAPN-induced mouse model of AD, intravenous administration of Antago-miR-155-5p-loaded M0-Exos significantly improved survival, reduced AD incidence and aortic dilation, and restored VSMC contractile markers. Biodistribution studies using DiR and CY5 labeling confirmed efficient accumulation of these engineered exosomes in the injured aorta, while macrophage depletion and rescue experiments validated the pathogenic role of M1-derived exosomes. These findings identify a novel M1 exosome-miR-155-5p-SMAD5/RHOA/ROCK signaling axis in AD and establish engineered M0 macrophage-derived exosomes as a promising bioactive material platform for targeted miRNA therapy in aortic dissection.
PMID:42389022 | PMC:PMC13320290 | DOI:10.1016/j.bioactmat.2026.05.057
Bioact Mater. 2026 Jun 24;65:984-1004. doi: 10.1016/j.bioactmat.2026.05.057. eCollection 2026 Nov.
ABSTRACT
Aortic dissection (AD) is a life-threatening cardiovascular emergency characterized by acute aortic wall injury and high mortality, yet effective pharmacological therapies remain limited. Macrophage infiltration and vascular smooth muscle cell (VSMC) phenotypic switching from contractile to synthetic states are central to AD pathogenesis, but the mechanisms mediating intercellular communication between macrophages and VSMCs are incompletely understood. Emerging evidence suggests that exosomes can transfer bioactive miRNAs between cells; however, whether M1 macrophage-derived exosomes promote AD progression through specific miRNA delivery and whether they can be engineered for therapeutic intervention have not been clearly defined. In this study, we demonstrate that M1 macrophage-derived exosomes deliver miR-155-5p to VSMCs, where it targets and suppresses SMAD5, activates the RHOA/ROCK pathway, and drives contractile-to-synthetic phenotypic switching, thereby accelerating AD progression. Through comprehensive physicochemical characterization, including TEM, NTA, Zeta potential, and stability assays, we show that M0 macrophage-derived exosomes can be successfully engineered to load Antago-miR-155-5p via electroporation with favorable encapsulation efficiency and colloidal stability. In a BAPN-induced mouse model of AD, intravenous administration of Antago-miR-155-5p-loaded M0-Exos significantly improved survival, reduced AD incidence and aortic dilation, and restored VSMC contractile markers. Biodistribution studies using DiR and CY5 labeling confirmed efficient accumulation of these engineered exosomes in the injured aorta, while macrophage depletion and rescue experiments validated the pathogenic role of M1-derived exosomes. These findings identify a novel M1 exosome-miR-155-5p-SMAD5/RHOA/ROCK signaling axis in AD and establish engineered M0 macrophage-derived exosomes as a promising bioactive material platform for targeted miRNA therapy in aortic dissection.
PMID:42389022 | PMC:PMC13320290 | DOI:10.1016/j.bioactmat.2026.05.057
Clin Exp Hypertens. 2026 Dec 31;48(1):2657354. doi: 10.1080/10641963.2026.2657354. Epub 2026 Jun 28.
ABSTRACT
OBJECTIVE: Aortic dissection (AD) is a fatal cardiovascular emergency that is predominantly induced by long-term uncontrolled hypertension.
MATERIALS AND METHODS: The mouse AD model was established by combining \u03b2-aminopropionitrile with angiotensin II. The incidence rate, rupture rate, and survival status of the mice were evaluated. The structural damage of the aorta was observed using tissue staining technology, the extracellular matrix status, and macrophage pyroptosis were evaluated by immunofluorescence staining, the infiltration of inflammatory cells was detected by immunohistochemistry, the expression of pyroptosis-related molecules, and inflammatory factors was analyzed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Cell proliferation was detected by EdU staining, and cell apoptosis was detected by flow cytometry.
RESULTS: In the aortic tissues of AD model mice, the expression of APN, and the content of APN in the serum were significantly decreased. APN intervention can alleviate the thickening of the aortic media, rupture of elastic fibers, and degradation of the extracellular matrix. APN inhibits the proliferation, apoptosis, and phenotypic transformation of vascular smooth muscle cells (VSMCs). At the same time, it can inhibit the infiltration of neutrophils and macrophages and the inflammatory response. Underlying mechanism, it was found that APN inhibited NLRP3-mediated pyroptosis by reducing the release of inflammatory factors; this effect was dependent on the phosphorylation activation of AMPK\u03b1 and APN receptor.
CONCLUSION: APN plays a protective role in AD. Its underlying mechanism is related to the activation of the AMPK pathway, which in turn inhibits macrophage pyroptosis and vascular inflammation. This study offers a new perspective for the pathological mechanism of AD.
PMID:42366506 | DOI:10.1080/10641963.2026.2657354
Clin Exp Hypertens. 2026 Dec 31;48(1):2657354. doi: 10.1080/10641963.2026.2657354. Epub 2026 Jun 28.
ABSTRACT
OBJECTIVE: Aortic dissection (AD) is a fatal cardiovascular emergency that is predominantly induced by long-term uncontrolled hypertension.
MATERIALS AND METHODS: The mouse AD model was established by combining \u03b2-aminopropionitrile with angiotensin II. The incidence rate, rupture rate, and survival status of the mice were evaluated. The structural damage of the aorta was observed using tissue staining technology, the extracellular matrix status, and macrophage pyroptosis were evaluated by immunofluorescence staining, the infiltration of inflammatory cells was detected by immunohistochemistry, the expression of pyroptosis-related molecules, and inflammatory factors was analyzed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Cell proliferation was detected by EdU staining, and cell apoptosis was detected by flow cytometry.
RESULTS: In the aortic tissues of AD model mice, the expression of APN, and the content of APN in the serum were significantly decreased. APN intervention can alleviate the thickening of the aortic media, rupture of elastic fibers, and degradation of the extracellular matrix. APN inhibits the proliferation, apoptosis, and phenotypic transformation of vascular smooth muscle cells (VSMCs). At the same time, it can inhibit the infiltration of neutrophils and macrophages and the inflammatory response. Underlying mechanism, it was found that APN inhibited NLRP3-mediated pyroptosis by reducing the release of inflammatory factors; this effect was dependent on the phosphorylation activation of AMPK\u03b1 and APN receptor.
CONCLUSION: APN plays a protective role in AD. Its underlying mechanism is related to the activation of the AMPK pathway, which in turn inhibits macrophage pyroptosis and vascular inflammation. This study offers a new perspective for the pathological mechanism of AD.
PMID:42366506 | DOI:10.1080/10641963.2026.2657354
Phytomedicine. 2026 Sep;159:158464. doi: 10.1016/j.phymed.2026.158464. Epub 2026 Jun 19.
ABSTRACT
BACKGROUND: Marfan syndrome (MFS) is a genetic disorder predominantly caused by mutations in the FBN1 gene, leading to thoracic aortic aneurysm (TAA) and a lack of effective pharmacological treatments. However, the role of metabolic alterations in this process remains poorly understood.
PURPOSE: We aim to investigate the regulatory roles of metabolites in MFS.
METHODS: Fbn1C1039G/+ mice were utilized as a TAA mouse model of MFS. Untargeted metabolomic screening of aortic tissues was conducted to identify metabolites in Fbn1C1039G/+ mice compared to controls. Echocardiographic and EVG staining were performed to evaluate TAA. Vascular smooth muscle cells (VSMCs) were isolated from mice for in vitro experiments. Proteomic sequencing was conducted to identify target mediators. Rescue experiments were carried out using recombinant LDHA in vitro.
RESULTS: Stachydrine (STA) was upregulated in Fbn1C1039G/+ mice aorta compared with controls. Administration of STA notably mitigated thoracic aortic dilation and medial degeneration in MFS mice. Furthermore, STA significantly diminished the elevated expression of matrix metalloproteinases and the excessive activation of the transforming growth factor-\u03b2 (TGF-\u03b2) signaling pathway in vivo and in vitro. Proteomic analysis revealed that STA treatment led to a reduction in lactate dehydrogenase A (LDHA) expression. Rescue experiments further confirmed that LDHA acts as a critical mediator downstream of STA.
CONCLUSIONS: STA attenuated TAA in MFS by inhibiting LDHA, thereby modulating TGF-\u03b2 signaling and maintaining extracellular matrix homeostasis. These findings highlight STA as a protective metabolite and suggest LDHA as a potential therapeutic factor for TAA in MFS.
PMID:42364561 | DOI:10.1016/j.phymed.2026.158464
Phytomedicine. 2026 Sep;159:158464. doi: 10.1016/j.phymed.2026.158464. Epub 2026 Jun 19.
ABSTRACT
BACKGROUND: Marfan syndrome (MFS) is a genetic disorder predominantly caused by mutations in the FBN1 gene, leading to thoracic aortic aneurysm (TAA) and a lack of effective pharmacological treatments. However, the role of metabolic alterations in this process remains poorly understood.
PURPOSE: We aim to investigate the regulatory roles of metabolites in MFS.
METHODS: Fbn1C1039G/+ mice were utilized as a TAA mouse model of MFS. Untargeted metabolomic screening of aortic tissues was conducted to identify metabolites in Fbn1C1039G/+ mice compared to controls. Echocardiographic and EVG staining were performed to evaluate TAA. Vascular smooth muscle cells (VSMCs) were isolated from mice for in vitro experiments. Proteomic sequencing was conducted to identify target mediators. Rescue experiments were carried out using recombinant LDHA in vitro.
RESULTS: Stachydrine (STA) was upregulated in Fbn1C1039G/+ mice aorta compared with controls. Administration of STA notably mitigated thoracic aortic dilation and medial degeneration in MFS mice. Furthermore, STA significantly diminished the elevated expression of matrix metalloproteinases and the excessive activation of the transforming growth factor-\u03b2 (TGF-\u03b2) signaling pathway in vivo and in vitro. Proteomic analysis revealed that STA treatment led to a reduction in lactate dehydrogenase A (LDHA) expression. Rescue experiments further confirmed that LDHA acts as a critical mediator downstream of STA.
CONCLUSIONS: STA attenuated TAA in MFS by inhibiting LDHA, thereby modulating TGF-\u03b2 signaling and maintaining extracellular matrix homeostasis. These findings highlight STA as a protective metabolite and suggest LDHA as a potential therapeutic factor for TAA in MFS.
PMID:42364561 | DOI:10.1016/j.phymed.2026.158464
J Cardiovasc Dev Dis. 2026 May 25;13(6):224. doi: 10.3390/jcdd13060224.
ABSTRACT
BACKGROUND: Immune dysregulation and clinical immunosuppression are biologically plausible contributors to thoracic aortic wall vulnerability through endothelial injury, protease-mediated extracellular matrix remodeling, vascular smooth muscle cell dysfunction, and impaired vascular repair. Yet, the clinical relevance of immunomodulated states to thoracic aortic aneurysm (TAA) incidence or growth and acute aortic syndromes remains undefined.
METHODS: This comprehensive review synthesizes clinical and translation evidence linking immunomodulated states in solid organ transplantation, autoimmune disease (predominantly systemic lupus erythematosus), HIV, and oncologic therapies to thoracic aortic dilation, aneurysmal progression, and acute aortic events.
PRINCIPAL FINDINGS: Across transplant, autoimmune, and HIV cohorts, recurring themes include chronic immune dysregulation, endothelial dysfunction, proteolytic matrix remodeling, and impaired vascular repair capacity, although thoracic segment-specific longitudinal growth data remain limited and are often embedded within analyses of multiple vascular beds. In oncologic cohorts, aggregate analyses generally do not demonstrate uniform acceleration of aneurysm growth with malignancy or chemotherapy exposure, although agent-level models suggest that regimen-specific effects may be obscured in pooled estimates. Two studies most directly addressed our question in thoracic-relevant contexts reported (1) very low mean annual ascending aortic aneurysm growth (0.18 \u00b1 0.64 mm/year) with no detectable association with chemotherapy or radiotherapy and (2) prior immunosuppressive/cytostatic chemotherapy exposure to be common in a proximal TAA surgical cohort (39.3%) without a clear difference in thoracic phenotype at presentation or postoperative outcomes. In HIV cohorts, available evidence supports modest but reproducible proximal aortic remodeling and a clinically meaningful aneurysm burden across vascular beds, yet definitive thoracic segment-specific natural history data remain limited.
CONCLUSIONS: The available literature supports clinical vigilance and exposure-aware surveillance, while suggesting that thoracic aortic risk is unlikely to be uniform across immunosuppressive and cytotoxic therapies. Standardized, segment-specific longitudinal imaging with granular agent-level exposure characterization (dose, duration, sequencing, and combination regimens), consistent definitions of baseline diameter and growth, careful adjustment for key confounders, and prospective ascertainment of dissection/rupture and operative endpoints are needed to translate immunobiology into actionable risk stratification and long-term management strategies.
PMID:42346444 | PMC:PMC13302154 | DOI:10.3390/jcdd13060224
J Cardiovasc Dev Dis. 2026 May 25;13(6):224. doi: 10.3390/jcdd13060224.
ABSTRACT
BACKGROUND: Immune dysregulation and clinical immunosuppression are biologically plausible contributors to thoracic aortic wall vulnerability through endothelial injury, protease-mediated extracellular matrix remodeling, vascular smooth muscle cell dysfunction, and impaired vascular repair. Yet, the clinical relevance of immunomodulated states to thoracic aortic aneurysm (TAA) incidence or growth and acute aortic syndromes remains undefined.
METHODS: This comprehensive review synthesizes clinical and translation evidence linking immunomodulated states in solid organ transplantation, autoimmune disease (predominantly systemic lupus erythematosus), HIV, and oncologic therapies to thoracic aortic dilation, aneurysmal progression, and acute aortic events.
PRINCIPAL FINDINGS: Across transplant, autoimmune, and HIV cohorts, recurring themes include chronic immune dysregulation, endothelial dysfunction, proteolytic matrix remodeling, and impaired vascular repair capacity, although thoracic segment-specific longitudinal growth data remain limited and are often embedded within analyses of multiple vascular beds. In oncologic cohorts, aggregate analyses generally do not demonstrate uniform acceleration of aneurysm growth with malignancy or chemotherapy exposure, although agent-level models suggest that regimen-specific effects may be obscured in pooled estimates. Two studies most directly addressed our question in thoracic-relevant contexts reported (1) very low mean annual ascending aortic aneurysm growth (0.18 \u00b1 0.64 mm/year) with no detectable association with chemotherapy or radiotherapy and (2) prior immunosuppressive/cytostatic chemotherapy exposure to be common in a proximal TAA surgical cohort (39.3%) without a clear difference in thoracic phenotype at presentation or postoperative outcomes. In HIV cohorts, available evidence supports modest but reproducible proximal aortic remodeling and a clinically meaningful aneurysm burden across vascular beds, yet definitive thoracic segment-specific natural history data remain limited.
CONCLUSIONS: The available literature supports clinical vigilance and exposure-aware surveillance, while suggesting that thoracic aortic risk is unlikely to be uniform across immunosuppressive and cytotoxic therapies. Standardized, segment-specific longitudinal imaging with granular agent-level exposure characterization (dose, duration, sequencing, and combination regimens), consistent definitions of baseline diameter and growth, careful adjustment for key confounders, and prospective ascertainment of dissection/rupture and operative endpoints are needed to translate immunobiology into actionable risk stratification and long-term management strategies.
PMID:42346444 | PMC:PMC13302154 | DOI:10.3390/jcdd13060224
Biochim Biophys Acta Mol Basis Dis. 2026 Oct;1872(7):168331. doi: 10.1016/j.bbadis.2026.168331. Epub 2026 Jun 24.
ABSTRACT
While emerging evidence highlights the importance of DNA methyltransferase 3B (DNMT3B) in cardiovascular pathophysiology, its precise role in thoracic aortic aneurysm and dissection (TAAD) remains poorly understood. Here, we elucidate the function and underlying mechanisms of DNMT3B in TAAD pathogenesis. We found that DNMT3B expression was markedly downregulated in vascular smooth muscle cells (VSMCs) of both human and mouse TAAD tissues compared to healthy controls. In vivo, targeted overexpression of DNMT3B in VSMCs via adeno-associated virus delivery significantly decreased TAAD incidence, reduced aortic rupture rates, and attenuated aortic dilation. Conversely, VSMC-specific DNMT3B knockdown exacerbated disease progression. In vitro experiments, utilizing adenovirus-mediated overexpression and the inhibitor Nanaomycin A revealed that DNMT3B inhibits both VSMC autophagy and phenotypic switching. Mechanistically, DNMT3B prevents the maladaptive transition of VSMCs toward a synthetic phenotype through the transcriptional repression of transcription factor EB (TFEB), thereby curbing excessive autophagy. Collectively, our findings demonstrate a protective role for DNMT3B against TAAD, highlighting its function in preserving VSMC homeostasis via the transcriptional inhibition of TFEB.
PMID:42342163 | DOI:10.1016/j.bbadis.2026.168331
Biochim Biophys Acta Mol Basis Dis. 2026 Oct;1872(7):168331. doi: 10.1016/j.bbadis.2026.168331. Epub 2026 Jun 24.
ABSTRACT
While emerging evidence highlights the importance of DNA methyltransferase 3B (DNMT3B) in cardiovascular pathophysiology, its precise role in thoracic aortic aneurysm and dissection (TAAD) remains poorly understood. Here, we elucidate the function and underlying mechanisms of DNMT3B in TAAD pathogenesis. We found that DNMT3B expression was markedly downregulated in vascular smooth muscle cells (VSMCs) of both human and mouse TAAD tissues compared to healthy controls. In vivo, targeted overexpression of DNMT3B in VSMCs via adeno-associated virus delivery significantly decreased TAAD incidence, reduced aortic rupture rates, and attenuated aortic dilation. Conversely, VSMC-specific DNMT3B knockdown exacerbated disease progression. In vitro experiments, utilizing adenovirus-mediated overexpression and the inhibitor Nanaomycin A revealed that DNMT3B inhibits both VSMC autophagy and phenotypic switching. Mechanistically, DNMT3B prevents the maladaptive transition of VSMCs toward a synthetic phenotype through the transcriptional repression of transcription factor EB (TFEB), thereby curbing excessive autophagy. Collectively, our findings demonstrate a protective role for DNMT3B against TAAD, highlighting its function in preserving VSMC homeostasis via the transcriptional inhibition of TFEB.
PMID:42342163 | DOI:10.1016/j.bbadis.2026.168331
J Cardiothorac Surg. 2026 Jun 23;21(1):685. doi: 10.1186/s13019-026-04445-7.
ABSTRACT
Aortic dissection (AD) is a devastating vascular disorder pathologically characterized by pathological phenotypic switching of medial vascular smooth muscle cells (VSMCs) and progressive breakdown of extracellular matrix (ECM) architecture. Conventional paradigms have primarily emphasized unidirectional injury originating within the vessel wall. Nevertheless, accumulating evidence indicates that perivascular adipose tissue (PVAT), which directly envelops the adventitia and is increasingly regarded as the \"fourth layer\" of the vascular wall, exerts a critical outside-in influence on vascular homeostasis and microenvironmental imbalance. This review systematically delineates how perivascular adipose tissue (PVAT) shifts from a vasoprotective component to a pathogenic source under conditions of local inflammation or metabolic stress. We particularly focus on the pathological state in which PVAT releases a broad array of pro-inflammatory mediators through paracrine signaling, most notably transforming growth factor-\u03b21 (TGF-\u03b21), which crosses tissue boundaries to orchestrate microenvironmental crosstalk between the adventitia and the media.Under persistent TGF-\u03b21 stimulation, vascular smooth muscle cells (VSMCs) may develop a cooperative transcriptional regulatory network centered on Runt-related transcription factor 1 (RUNX1) and nuclear factor-\u03baB (NF-\u03baB). This review explores the hypothesis that PVAT-derived inflammatory stimuli may induce post-receptor TGF-\u03b21 signal shunting, thereby favoring the formation of a RUNX1/NF-\u03baB regulatory axis in VSMCs. Such a network may contribute to aortic wall destabilization by suppressing contractile phenotype-associated genes while promoting inflammatory and extracellular matrix remodeling programs. From an \"outside-in\" perspective, we discuss the potential role of PVAT-VSMC microenvironmental crosstalk in AD pathogenesis and critically evaluate the current evidence supporting this model, as well as its limitations. Furthermore, we propose that future therapeutic strategies targeting this transcriptional axis may require localized delivery approaches to minimize systemic adverse effects, including bleeding and immunosuppression, thereby offering a potential avenue for precision treatment of AD.
PMID:42337688 | PMC:PMC13560320 | DOI:10.1186/s13019-026-04445-7
J Cardiothorac Surg. 2026 Jun 23;21(1):685. doi: 10.1186/s13019-026-04445-7.
ABSTRACT
Aortic dissection (AD) is a devastating vascular disorder pathologically characterized by pathological phenotypic switching of medial vascular smooth muscle cells (VSMCs) and progressive breakdown of extracellular matrix (ECM) architecture. Conventional paradigms have primarily emphasized unidirectional injury originating within the vessel wall. Nevertheless, accumulating evidence indicates that perivascular adipose tissue (PVAT), which directly envelops the adventitia and is increasingly regarded as the \"fourth layer\" of the vascular wall, exerts a critical outside-in influence on vascular homeostasis and microenvironmental imbalance. This review systematically delineates how perivascular adipose tissue (PVAT) shifts from a vasoprotective component to a pathogenic source under conditions of local inflammation or metabolic stress. We particularly focus on the pathological state in which PVAT releases a broad array of pro-inflammatory mediators through paracrine signaling, most notably transforming growth factor-\u03b21 (TGF-\u03b21), which crosses tissue boundaries to orchestrate microenvironmental crosstalk between the adventitia and the media.Under persistent TGF-\u03b21 stimulation, vascular smooth muscle cells (VSMCs) may develop a cooperative transcriptional regulatory network centered on Runt-related transcription factor 1 (RUNX1) and nuclear factor-\u03baB (NF-\u03baB). This review explores the hypothesis that PVAT-derived inflammatory stimuli may induce post-receptor TGF-\u03b21 signal shunting, thereby favoring the formation of a RUNX1/NF-\u03baB regulatory axis in VSMCs. Such a network may contribute to aortic wall destabilization by suppressing contractile phenotype-associated genes while promoting inflammatory and extracellular matrix remodeling programs. From an \"outside-in\" perspective, we discuss the potential role of PVAT-VSMC microenvironmental crosstalk in AD pathogenesis and critically evaluate the current evidence supporting this model, as well as its limitations. Furthermore, we propose that future therapeutic strategies targeting this transcriptional axis may require localized delivery approaches to minimize systemic adverse effects, including bleeding and immunosuppression, thereby offering a potential avenue for precision treatment of AD.
PMID:42337688 | PMC:PMC13560320 | DOI:10.1186/s13019-026-04445-7
J Mol Med (Berl). 2026 Jun 23;104(1):89. doi: 10.1007/s00109-026-02696-4.
ABSTRACT
Aortic dissection (AD) is a life-threatening vascular emergency characterized by medial degeneration and vascular smooth muscle cell (VSMC) loss. Although disruption of zinc homeostasis has been reported in patients with AD, how zinc ions and their regulatory proteins influence VSMC survival and disease progression remains unknown. In this study, single-cell analyses revealed that ferroptosis and zinc-related pathways were significantly enriched in VSMCs from patients with AD, showing a strong correlation between the two processes, and zinc levels were markedly elevated in dissected aortas. Furthermore, zinc exposure promoted ferroptosis in cultured primary human aortic smooth muscle cells (HASMCs). By integrating transcriptomic data from AD tissues and VSMC ferroptosis models, metallothionein-3 (MT3), a zinc-binding protein, was identified as a candidate regulator. Functional studies demonstrated that MT3 overexpression markedly attenuated lipid peroxidation, reduced reactive oxygen species accumulation, and protected VSMCs from ferroptotic cell death, whereas MT3 knockdown increased oxidative stress and exacerbated ferroptotic injury. Mechanistically, MT3 directly interacted with glutathione peroxidase 4 (GPX4), enhanced its protein stability, without altering its transcriptional expression, and promoted glutathione synthesis, thereby activating the glutathione-GPX4 antioxidant defense pathway and mitigating oxidative injury. Notably, restoration of GPX4 effectively rescued the pro-ferroptotic effects of MT3 deficiency on HASMCs. These findings establish a previously unrecognized zinc-MT3-GPX4 axis as a critical determinant of VSMC ferroptosis in AD, linking zinc dysregulation to medial degeneration, and highlighting MT3 as a potential mechanistic candidate target to preserve vascular integrity and limit disease progression. KEY MESSAGES: Impaired zinc homeostasis is implicated in the development of aortic dissection (AD). Zinc-binding protein metallothionein 3 (MT3) mitigates lipid peroxidation and protects vascular smooth muscle cells from ferroptosis. MT3 directly interacts with glutathione peroxidase 4 (GPX4) to prevent its lysosomal degradation, thereby enhancing the glutathione-GPX4 antioxidant defense pathway. MT3 is a potential mechanistic candidate target for preserving vascular integrity and limiting AD progression.
PMID:42334628 | PMC:PMC13290830 | DOI:10.1007/s00109-026-02696-4
J Mol Med (Berl). 2026 Jun 23;104(1):89. doi: 10.1007/s00109-026-02696-4.
ABSTRACT
Aortic dissection (AD) is a life-threatening vascular emergency characterized by medial degeneration and vascular smooth muscle cell (VSMC) loss. Although disruption of zinc homeostasis has been reported in patients with AD, how zinc ions and their regulatory proteins influence VSMC survival and disease progression remains unknown. In this study, single-cell analyses revealed that ferroptosis and zinc-related pathways were significantly enriched in VSMCs from patients with AD, showing a strong correlation between the two processes, and zinc levels were markedly elevated in dissected aortas. Furthermore, zinc exposure promoted ferroptosis in cultured primary human aortic smooth muscle cells (HASMCs). By integrating transcriptomic data from AD tissues and VSMC ferroptosis models, metallothionein-3 (MT3), a zinc-binding protein, was identified as a candidate regulator. Functional studies demonstrated that MT3 overexpression markedly attenuated lipid peroxidation, reduced reactive oxygen species accumulation, and protected VSMCs from ferroptotic cell death, whereas MT3 knockdown increased oxidative stress and exacerbated ferroptotic injury. Mechanistically, MT3 directly interacted with glutathione peroxidase 4 (GPX4), enhanced its protein stability, without altering its transcriptional expression, and promoted glutathione synthesis, thereby activating the glutathione-GPX4 antioxidant defense pathway and mitigating oxidative injury. Notably, restoration of GPX4 effectively rescued the pro-ferroptotic effects of MT3 deficiency on HASMCs. These findings establish a previously unrecognized zinc-MT3-GPX4 axis as a critical determinant of VSMC ferroptosis in AD, linking zinc dysregulation to medial degeneration, and highlighting MT3 as a potential mechanistic candidate target to preserve vascular integrity and limit disease progression. KEY MESSAGES: Impaired zinc homeostasis is implicated in the development of aortic dissection (AD). Zinc-binding protein metallothionein 3 (MT3) mitigates lipid peroxidation and protects vascular smooth muscle cells from ferroptosis. MT3 directly interacts with glutathione peroxidase 4 (GPX4) to prevent its lysosomal degradation, thereby enhancing the glutathione-GPX4 antioxidant defense pathway. MT3 is a potential mechanistic candidate target for preserving vascular integrity and limiting AD progression.
PMID:42334628 | PMC:PMC13290830 | DOI:10.1007/s00109-026-02696-4
Mol Med Rep. 2026 Aug;34(2):232. doi: 10.3892/mmr.2026.13942. Epub 2026 Jun 19.
ABSTRACT
Thoracic aortic aneurysm and dissection (TAAD) is a life\u2011threatening disease with an insidious onset and a largely elusive pathogenesis. Hereditary TAAD (HTAD) can be classified into syndromic forms, including Marfan syndrome, Loeys\u2011Dietz syndrome and vascular Ehlers\u2011Danlos syndrome and non\u2011syndromic forms, including familial TAAD and bicuspid aortic valve\u2011associated TAAD. Current evidence suggests that HTAD development shares several core mechanisms, including extracellular matrix disruption, dysregulated transforming growth factor\u2011\u03b2 signaling, vascular smooth muscle cell dysfunction and, in the case of bicuspid aortic valve, abnormal hemodynamic stress. The present review summarizes the major genes and molecular pathways involved in HTAD and discusses their contributions to disease progression. Elucidating the underlying mechanisms associated with HTAD may facilitate risk assessment and the development of targeted therapies.
PMID:42318957 | PMC:PMC13311905 | DOI:10.3892/mmr.2026.13942
Mol Med Rep. 2026 Aug;34(2):232. doi: 10.3892/mmr.2026.13942. Epub 2026 Jun 19.
ABSTRACT
Thoracic aortic aneurysm and dissection (TAAD) is a life\u2011threatening disease with an insidious onset and a largely elusive pathogenesis. Hereditary TAAD (HTAD) can be classified into syndromic forms, including Marfan syndrome, Loeys\u2011Dietz syndrome and vascular Ehlers\u2011Danlos syndrome and non\u2011syndromic forms, including familial TAAD and bicuspid aortic valve\u2011associated TAAD. Current evidence suggests that HTAD development shares several core mechanisms, including extracellular matrix disruption, dysregulated transforming growth factor\u2011\u03b2 signaling, vascular smooth muscle cell dysfunction and, in the case of bicuspid aortic valve, abnormal hemodynamic stress. The present review summarizes the major genes and molecular pathways involved in HTAD and discusses their contributions to disease progression. Elucidating the underlying mechanisms associated with HTAD may facilitate risk assessment and the development of targeted therapies.
PMID:42318957 | PMC:PMC13311905 | DOI:10.3892/mmr.2026.13942
BMC Med Genomics. 2026 Jun 13;19(1):134. doi: 10.1186/s12920-026-02410-w.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disease with limited effective therapeutic options. Phenotypic switching of aortic vascular smooth muscle cells (VSMCs) from a contractile to a pathological state is a critical driver of AD progression. However, the molecular regulators governing this transition remain incompletely understood. This study aimed to identify a critical regulator of VSMC phenotypic switching in AD and to investigate its underlying mechanisms and translational relevance.
METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets obtained from the Gene Expression Omnibus (GEO) database were integrated for analysis. To enhance robustness and reduce dataset-specific bias, weighted gene co-expression network analysis (WGCNA) was performed in both aortic aneurysm (AA) and AD cohorts to identify gene modules associated with VSMC function. Overlapping VSMC-related modules were intersected to define candidate genes. Key regulators were further prioritized in AD datasets using LASSO regression and validated by single-cell RNA sequencing (scRNA-seq) pseudotime trajectory analysis to delineate dynamic gene expression during VSMC phenotypic switching. Functional validation was conducted in an angiotensin II (Ang II)-induced experimental AD mouse model with AAV9-mediated CASQ2 overexpression, as well as in primary VSMCs isolated from the abdominal aorta of mice and treated with Ang II in vitro. Aortic morphology, medial calcification, VSMC phenotypic markers, intracellular Ca2+ homeostasis, and endoplasmic reticulum (ER) stress signaling were systematically evaluated.
RESULTS: WGCNA identified a conserved gene module comprising 64 genes associated with VSMC phenotypic transition. Integrative LASSO and scRNA-seq analyses prioritized CASQ2 as a key gene with reduced expression in AD VSMCs. Pseudotime analysis revealed progressive downregulation of CASQ2 during osteochondrogenic phenotypic switching. In AngII-induced experimental AD mice, CASQ2 expression was decreased in the aortic media and accompanied by enhanced medial calcification. In vivo, Ang II infusion markedly reduced aortic CASQ2 expression and induced medial dilation and calcification, accompanied by increased mortality. AAV9-mediated CASQ2 overexpression significantly improved survival, attenuated aneurysmal enlargement, reduced vascular calcification and partially restored contractile marker expression. In vitro, Ang II stimulation decreased CASQ2 levels in primary VSMCs, promoted osteochondrogenic marker expression, and induced intracellular Ca\u00b2\u207a overload. CASQ2 overexpression restored calcium-release complex components, suppressed cytosolic Ca\u00b2\u207a elevation, and markedly reduced ER stress activation.
CONCLUSIONS: CASQ2 may represent a VSMC-enriched functional regulator involved in AD-associated phenotypic switching through calcium homeostasis and ER stress. These findings suggest that CASQ2 represents a potential therapeutic target in AD. Further studies are needed to determine its disease specificity and translational relevance.
PMID:42288847 | PMC:PMC13491616 | DOI:10.1186/s12920-026-02410-w
BMC Med Genomics. 2026 Jun 13;19(1):134. doi: 10.1186/s12920-026-02410-w.
ABSTRACT
BACKGROUND: Aortic dissection (AD) is a life-threatening cardiovascular disease with limited effective therapeutic options. Phenotypic switching of aortic vascular smooth muscle cells (VSMCs) from a contractile to a pathological state is a critical driver of AD progression. However, the molecular regulators governing this transition remain incompletely understood. This study aimed to identify a critical regulator of VSMC phenotypic switching in AD and to investigate its underlying mechanisms and translational relevance.
METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets obtained from the Gene Expression Omnibus (GEO) database were integrated for analysis. To enhance robustness and reduce dataset-specific bias, weighted gene co-expression network analysis (WGCNA) was performed in both aortic aneurysm (AA) and AD cohorts to identify gene modules associated with VSMC function. Overlapping VSMC-related modules were intersected to define candidate genes. Key regulators were further prioritized in AD datasets using LASSO regression and validated by single-cell RNA sequencing (scRNA-seq) pseudotime trajectory analysis to delineate dynamic gene expression during VSMC phenotypic switching. Functional validation was conducted in an angiotensin II (Ang II)-induced experimental AD mouse model with AAV9-mediated CASQ2 overexpression, as well as in primary VSMCs isolated from the abdominal aorta of mice and treated with Ang II in vitro. Aortic morphology, medial calcification, VSMC phenotypic markers, intracellular Ca2+ homeostasis, and endoplasmic reticulum (ER) stress signaling were systematically evaluated.
RESULTS: WGCNA identified a conserved gene module comprising 64 genes associated with VSMC phenotypic transition. Integrative LASSO and scRNA-seq analyses prioritized CASQ2 as a key gene with reduced expression in AD VSMCs. Pseudotime analysis revealed progressive downregulation of CASQ2 during osteochondrogenic phenotypic switching. In AngII-induced experimental AD mice, CASQ2 expression was decreased in the aortic media and accompanied by enhanced medial calcification. In vivo, Ang II infusion markedly reduced aortic CASQ2 expression and induced medial dilation and calcification, accompanied by increased mortality. AAV9-mediated CASQ2 overexpression significantly improved survival, attenuated aneurysmal enlargement, reduced vascular calcification and partially restored contractile marker expression. In vitro, Ang II stimulation decreased CASQ2 levels in primary VSMCs, promoted osteochondrogenic marker expression, and induced intracellular Ca\u00b2\u207a overload. CASQ2 overexpression restored calcium-release complex components, suppressed cytosolic Ca\u00b2\u207a elevation, and markedly reduced ER stress activation.
CONCLUSIONS: CASQ2 may represent a VSMC-enriched functional regulator involved in AD-associated phenotypic switching through calcium homeostasis and ER stress. These findings suggest that CASQ2 represents a potential therapeutic target in AD. Further studies are needed to determine its disease specificity and translational relevance.
PMID:42288847 | PMC:PMC13491616 | DOI:10.1186/s12920-026-02410-w
Life Med. 2026 Apr 17;5(3):lnag013. doi: 10.1093/lifemedi/lnag013. eCollection 2026 Jun.
ABSTRACT
Aortic dissection (AD) is a fatal emergency which lacks effective drug therapies. Previous studies demonstrated that histone deacetylase 8 (HDAC8) inhibition provides protective benefits in several cardiovascular diseases, including heart failure, fibrosis, and cardiac hypertrophy. However, the role of HDAC8 in AD remains unclear. In the present study, we investigated the function of PCI-34051, a highly selective inhibitor of HDAC8, in human aortic smooth muscle cell (HASMC) ferroptosis and \u03b2-aminopropionitrile (BAPN)-induced AD in mice. The results showed that PCI-34051 and HDAC8 knockdown significantly inhibited cystine deprivation (CD)- and imidazole ketone erastin (IKE)-induced HASMC ferroptosis, as evidenced by an increase in cell viability, reduction in cell injury/death, and lipid peroxidation levels in HASMCs. Transcriptome sequencing analysis revealed that the anti-ferroptosis effect of PCI-34051 was associated with the regulation of activator protein-1 (AP-1). Additionally, co-immunoprecipitation results showed that HDAC8 interacts with c-JUN, a component of AP-1. Overexpression of AP-1 (c-FOS and c-JUN) largely abolished the inhibitory effects of PCI-34051 on HASMC ferroptosis. More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis.
PMID:42281825 | PMC:PMC13250666 | DOI:10.1093/lifemedi/lnag013
Life Med. 2026 Apr 17;5(3):lnag013. doi: 10.1093/lifemedi/lnag013. eCollection 2026 Jun.
ABSTRACT
Aortic dissection (AD) is a fatal emergency which lacks effective drug therapies. Previous studies demonstrated that histone deacetylase 8 (HDAC8) inhibition provides protective benefits in several cardiovascular diseases, including heart failure, fibrosis, and cardiac hypertrophy. However, the role of HDAC8 in AD remains unclear. In the present study, we investigated the function of PCI-34051, a highly selective inhibitor of HDAC8, in human aortic smooth muscle cell (HASMC) ferroptosis and \u03b2-aminopropionitrile (BAPN)-induced AD in mice. The results showed that PCI-34051 and HDAC8 knockdown significantly inhibited cystine deprivation (CD)- and imidazole ketone erastin (IKE)-induced HASMC ferroptosis, as evidenced by an increase in cell viability, reduction in cell injury/death, and lipid peroxidation levels in HASMCs. Transcriptome sequencing analysis revealed that the anti-ferroptosis effect of PCI-34051 was associated with the regulation of activator protein-1 (AP-1). Additionally, co-immunoprecipitation results showed that HDAC8 interacts with c-JUN, a component of AP-1. Overexpression of AP-1 (c-FOS and c-JUN) largely abolished the inhibitory effects of PCI-34051 on HASMC ferroptosis. More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis.
PMID:42281825 | PMC:PMC13250666 | DOI:10.1093/lifemedi/lnag013
Biol Direct. 2026 Jun 9;21(1):146. doi: 10.1186/s13062-026-00858-5.
ABSTRACT
BACKGROUND: Thoracic aortic aneurysm (TAA) is a life-threatening vascular condition with limitedpharmacological interventions. This study aimed to identify novel causaldruggable genes and therapeutic candidates for TAA.
METHODS: We performed Mendelian randomization (MR) by integrating cis-expression quantitativetrait loci (eQTL) and genome-wide association studies (GWAS) data to identifycausal genes for TAA. Therapeutic candidates were predicted via the DrugSignatures Database (DSigDB) and prioritized using molecular docking. Theclinical relevance of the lead target, STK33, was assessed in human TAA tissuesusing immunohistochemistry (IHC). The therapeutic efficacy of piceatannol wasrigorously validated across three distinct platforms: Angiotensin II(AngII)-stimulated vascular smooth muscle cells (VSMCs), and two complementaryanimal models (BAPN-induced and AngII-infused TAA mice).
RESULTS: MR analysis identified 31 druggable genes significantly associated with TAA risk.Integration with DSigDB and molecular docking pinpointed piceatannol as a potentcandidate targeting STK33. IHC staining revealed that STK33 expression wasmarkedly downregulated in human TAA tissues, a trend consistently observed inAngII-stimulated VSMCs and mouse TAA models. In vivo, piceatannol treatmentsignificantly reduced TAA incidence, mortality, and aortic dilation in bothBAPN-induced and AngII-induced mouse models. Mechanistically, piceatannoleffectively restored STK33 protein levels and attenuated the loss of VSMCcontractile markers (MYH11, \u03b1-SMA, and CNN1) both in vivo and invitro. These protective effects were largely abolished by STK33 knockdown,confirming a target-specific mechanism.
CONCLUSIONS: Piceatannol attenuates TAA progression, potentially through targeting and stabilizing STK33 expression. By utilizing a multi-model validation strategy (two in vivo modelsand an in vitro cell model), our findings highlight the piceatannol-STK33 axisas a promising therapeutic candidate for TAA.
PMID:42265708 | PMC:PMC13480056 | DOI:10.1186/s13062-026-00858-5
Biol Direct. 2026 Jun 9;21(1):146. doi: 10.1186/s13062-026-00858-5.
ABSTRACT
BACKGROUND: Thoracic aortic aneurysm (TAA) is a life-threatening vascular condition with limitedpharmacological interventions. This study aimed to identify novel causaldruggable genes and therapeutic candidates for TAA.
METHODS: We performed Mendelian randomization (MR) by integrating cis-expression quantitativetrait loci (eQTL) and genome-wide association studies (GWAS) data to identifycausal genes for TAA. Therapeutic candidates were predicted via the DrugSignatures Database (DSigDB) and prioritized using molecular docking. Theclinical relevance of the lead target, STK33, was assessed in human TAA tissuesusing immunohistochemistry (IHC). The therapeutic efficacy of piceatannol wasrigorously validated across three distinct platforms: Angiotensin II(AngII)-stimulated vascular smooth muscle cells (VSMCs), and two complementaryanimal models (BAPN-induced and AngII-infused TAA mice).
RESULTS: MR analysis identified 31 druggable genes significantly associated with TAA risk.Integration with DSigDB and molecular docking pinpointed piceatannol as a potentcandidate targeting STK33. IHC staining revealed that STK33 expression wasmarkedly downregulated in human TAA tissues, a trend consistently observed inAngII-stimulated VSMCs and mouse TAA models. In vivo, piceatannol treatmentsignificantly reduced TAA incidence, mortality, and aortic dilation in bothBAPN-induced and AngII-induced mouse models. Mechanistically, piceatannoleffectively restored STK33 protein levels and attenuated the loss of VSMCcontractile markers (MYH11, \u03b1-SMA, and CNN1) both in vivo and invitro. These protective effects were largely abolished by STK33 knockdown,confirming a target-specific mechanism.
CONCLUSIONS: Piceatannol attenuates TAA progression, potentially through targeting and stabilizing STK33 expression. By utilizing a multi-model validation strategy (two in vivo modelsand an in vitro cell model), our findings highlight the piceatannol-STK33 axisas a promising therapeutic candidate for TAA.
PMID:42265708 | PMC:PMC13480056 | DOI:10.1186/s13062-026-00858-5
Circ Res. 2026 Jul 6;139(2):e327965. doi: 10.1161/CIRCRESAHA.125.327965. Epub 2026 Jun 4.
ABSTRACT
BACKGROUND: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. ATAD3A (ATPase family AAA [ATPases associated with diverse cellular activities] domain-containing protein 3A), a mitochondrial AAA+ ATPase enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear.
METHODS: AAD was induced in wild-type, ATAD3A knock-in, and vascular smooth muscle cell (VSMC)-specific knockdown mice generated using short hairpin RNA against ATAD3A (sh-ATAD3A) by 3-week \u03b2-aminopropionitrile monofumarate intake or 28-day AngII (angiotensin II) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. Vascular smooth muscle cells were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca2+ imaging. ATAD3A-DLST (dihydrolipoamide S-succinyltransferase) interaction was examined by coimmunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate and the lipoylation inhibitor devimistat.
RESULTS: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in \u03b2-aminopropionitrile monofumarate-treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated \u03b2-aminopropionitrile monofumarate-induced and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca2+ influx, and suppressed the FDXR (ferredoxin reductase)/FDX1 (ferredoxin 1)/LIAS (lipoic acid synthetase) lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using tetrathiomolybdate or Devimistat attenuated disease severity in vivo.
CONCLUSIONS: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca2+ influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.
PMID:42237912 | DOI:10.1161/CIRCRESAHA.125.327965
Circ Res. 2026 Jul 6;139(2):e327965. doi: 10.1161/CIRCRESAHA.125.327965. Epub 2026 Jun 4.
ABSTRACT
BACKGROUND: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. ATAD3A (ATPase family AAA [ATPases associated with diverse cellular activities] domain-containing protein 3A), a mitochondrial AAA+ ATPase enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear.
METHODS: AAD was induced in wild-type, ATAD3A knock-in, and vascular smooth muscle cell (VSMC)-specific knockdown mice generated using short hairpin RNA against ATAD3A (sh-ATAD3A) by 3-week \u03b2-aminopropionitrile monofumarate intake or 28-day AngII (angiotensin II) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. Vascular smooth muscle cells were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca2+ imaging. ATAD3A-DLST (dihydrolipoamide S-succinyltransferase) interaction was examined by coimmunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate and the lipoylation inhibitor devimistat.
RESULTS: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in \u03b2-aminopropionitrile monofumarate-treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated \u03b2-aminopropionitrile monofumarate-induced and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca2+ influx, and suppressed the FDXR (ferredoxin reductase)/FDX1 (ferredoxin 1)/LIAS (lipoic acid synthetase) lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using tetrathiomolybdate or Devimistat attenuated disease severity in vivo.
CONCLUSIONS: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca2+ influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.
PMID:42237912 | DOI:10.1161/CIRCRESAHA.125.327965
Int Immunopharmacol. 2026 Sep 1;184:116937. doi: 10.1016/j.intimp.2026.116937. Epub 2026 Jun 2.
ABSTRACT
Aortic dissection (AD) represents a critical cardiovascular emergency characterized by high mortality and a lack of effective pharmacological interventions. This study investigates the role of ferroptosis, an iron-dependent regulated cell death characterized by lipid peroxidation, in the pathogenesis of AD, with a particular focus on the therapeutic efficacy of chlorogenic acid (CA), a natural phenolic compound with established antioxidant and anti-inflammatory activities. Using an atherosclerotic male ApoE-/- mouse model subjected to a high-fat diet and angiotensin II infusion, we evaluated the effects of CA treatment (50 or 100 mg/kg/day) on AD incidence, mortality, and various pathophysiological parameters. Our findings indicate that CA significantly reduces AD incidence and mortality in a dose-dependent manner, mitigating aortic medial degeneration, elastic fiber fragmentation, and lipid accumulation. Immunofluorescence co-staining further revealed that CA markedly reduced 4-hydroxynonenal (4-HNE) accumulation in \u03b1-smooth muscle actin (\u03b1-SMA)-positive mouse aortic vascular smooth muscle cells (MOVAS), confirming VSMC-specific inhibition of ferroptosis. Mechanistically, CA inhibits ferroptotic damage by reducing mitochondrial shrinkage and reactive oxygen species (ROS) production, while restoring the expression of key ferroptosis-related markers in the Nrf2/HO-1/GPX4 signaling axis. Pharmacological inhibition of Nrf2 using ML385 abolished these CA-mediated protective effects, verifying the essential role of Nrf2 signaling in the anti-ferroptotic action of CA. Corroborating these findings, transcriptomic profiling identified ferroptosis as a pivotal driver of AD, and in vitro experiments demonstrated that CA enhances the viability of MOVAS while inhibiting ferroptosis. In conclusion, this study highlights CA as a promising therapeutic agent for preventing and treating AD, elucidating its action via MOVAS specific ferroptosis inhibition through the Nrf2/HO-1/GPX4 axis, thereby suggesting that targeting ferroptosis may offer novel strategies for aortic wall protection in AD.
PMID:42229204 | DOI:10.1016/j.intimp.2026.116937
Int Immunopharmacol. 2026 Sep 1;184:116937. doi: 10.1016/j.intimp.2026.116937. Epub 2026 Jun 2.
ABSTRACT
Aortic dissection (AD) represents a critical cardiovascular emergency characterized by high mortality and a lack of effective pharmacological interventions. This study investigates the role of ferroptosis, an iron-dependent regulated cell death characterized by lipid peroxidation, in the pathogenesis of AD, with a particular focus on the therapeutic efficacy of chlorogenic acid (CA), a natural phenolic compound with established antioxidant and anti-inflammatory activities. Using an atherosclerotic male ApoE-/- mouse model subjected to a high-fat diet and angiotensin II infusion, we evaluated the effects of CA treatment (50 or 100 mg/kg/day) on AD incidence, mortality, and various pathophysiological parameters. Our findings indicate that CA significantly reduces AD incidence and mortality in a dose-dependent manner, mitigating aortic medial degeneration, elastic fiber fragmentation, and lipid accumulation. Immunofluorescence co-staining further revealed that CA markedly reduced 4-hydroxynonenal (4-HNE) accumulation in \u03b1-smooth muscle actin (\u03b1-SMA)-positive mouse aortic vascular smooth muscle cells (MOVAS), confirming VSMC-specific inhibition of ferroptosis. Mechanistically, CA inhibits ferroptotic damage by reducing mitochondrial shrinkage and reactive oxygen species (ROS) production, while restoring the expression of key ferroptosis-related markers in the Nrf2/HO-1/GPX4 signaling axis. Pharmacological inhibition of Nrf2 using ML385 abolished these CA-mediated protective effects, verifying the essential role of Nrf2 signaling in the anti-ferroptotic action of CA. Corroborating these findings, transcriptomic profiling identified ferroptosis as a pivotal driver of AD, and in vitro experiments demonstrated that CA enhances the viability of MOVAS while inhibiting ferroptosis. In conclusion, this study highlights CA as a promising therapeutic agent for preventing and treating AD, elucidating its action via MOVAS specific ferroptosis inhibition through the Nrf2/HO-1/GPX4 axis, thereby suggesting that targeting ferroptosis may offer novel strategies for aortic wall protection in AD.
PMID:42229204 | DOI:10.1016/j.intimp.2026.116937
Clin Exp Pharmacol Physiol. 2026 Jun;53(6):e70128. doi: 10.1111/1440-1681.70128.
ABSTRACT
Marfan syndrome (Mfs) arises from mutations in FBN1, predisposing individuals to thoracic aortic aneurysm (TAA) through abnormal smooth muscle cell behaviour. The role of HSPB7 in Mfs-related TAA remains poorly understood. By integrating multi-omics analysis with hiPSC-derived VSMCs from patients with Mfs, we elucidated the molecular landscape of Mfs-associated TAA. Analysis revealed immune cell infiltration, a reduced proportion of VSMCs, and altered intercellular communication. Pathway analyses indicated changes in cell adhesion, extracellular matrix (ECM) remodelling, and immune signalling, with downregulated metabolic pathways. Findings suggest structural, immune, and metabolic imbalances in Mfs-TAA pathogenesis. Downregulation of HSPB7 was associated with altered proliferation, migration, and metabolic activity. Overexpression of HSPB7 in patient-specific hiPSC-derived VSMCs attenuated these pathological features and promoted a more contractile phenotype. These findings suggest that HSPB7 may be involved in the regulation of VSMCs' phenotypic modulation in Mfs-TAA and provide mechanistic insight into disease-associated cellular alterations.
PMID:42203489 | DOI:10.1111/1440-1681.70128
Clin Exp Pharmacol Physiol. 2026 Jun;53(6):e70128. doi: 10.1111/1440-1681.70128.
ABSTRACT
Marfan syndrome (Mfs) arises from mutations in FBN1, predisposing individuals to thoracic aortic aneurysm (TAA) through abnormal smooth muscle cell behaviour. The role of HSPB7 in Mfs-related TAA remains poorly understood. By integrating multi-omics analysis with hiPSC-derived VSMCs from patients with Mfs, we elucidated the molecular landscape of Mfs-associated TAA. Analysis revealed immune cell infiltration, a reduced proportion of VSMCs, and altered intercellular communication. Pathway analyses indicated changes in cell adhesion, extracellular matrix (ECM) remodelling, and immune signalling, with downregulated metabolic pathways. Findings suggest structural, immune, and metabolic imbalances in Mfs-TAA pathogenesis. Downregulation of HSPB7 was associated with altered proliferation, migration, and metabolic activity. Overexpression of HSPB7 in patient-specific hiPSC-derived VSMCs attenuated these pathological features and promoted a more contractile phenotype. These findings suggest that HSPB7 may be involved in the regulation of VSMCs' phenotypic modulation in Mfs-TAA and provide mechanistic insight into disease-associated cellular alterations.
PMID:42203489 | DOI:10.1111/1440-1681.70128
FASEB J. 2026 Jun 15;40(11):e71979. doi: 10.1096/fj.202600149R.
ABSTRACT
Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with limited pharmacological treatments. Vascular smooth muscle cell (VSMC) loss is a critical pathological feature of TAD. Roxadustat (ROX), a HIF stabilizer for renal anemia, was evaluated in a \u03b2-aminopropionitrile (BAPN)-induced TAD mouse model. It significantly improved survival, attenuated weight loss and aortic dilation, decreased the incidence of TAD, alleviated elastic fibers damage, and ultimately inhibited TAD progression. Mechanistically, ROX upregulated HIF-1\u03b1 expression, reduced vascular wall iron deposition and lipid peroxidation products (MDA, 4-HNE), and normalized aberrant expression of ferroptosis markers ACSL4, TFR1, GPX4 and FTH1. In vitro, it mitigated Erastin/Ang II-induced VSMC ferroptosis, improved mitochondrial structure and function by enhancing oxygen consumption rate (OCR), restoring membrane potential, reducing reactive oxygen species (ROS), and boosting mitophagy via upregulating HIF-1\u03b1 and mitophagy markers (PINK1, Parkin). The HIF-1\u03b1 inhibitor KC7F2 and siHIF-1\u03b1 reversed these effects. Taken together, our findings demonstrate that ROX protects against TAD by promoting HIF-1\u03b1 expression to enhance mitophagy and inhibit VSMC ferroptosis, offering potential clinical implications for TAD prevention and treatment.
PMID:42201682 | DOI:10.1096/fj.202600149R
FASEB J. 2026 Jun 15;40(11):e71979. doi: 10.1096/fj.202600149R.
ABSTRACT
Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with limited pharmacological treatments. Vascular smooth muscle cell (VSMC) loss is a critical pathological feature of TAD. Roxadustat (ROX), a HIF stabilizer for renal anemia, was evaluated in a \u03b2-aminopropionitrile (BAPN)-induced TAD mouse model. It significantly improved survival, attenuated weight loss and aortic dilation, decreased the incidence of TAD, alleviated elastic fibers damage, and ultimately inhibited TAD progression. Mechanistically, ROX upregulated HIF-1\u03b1 expression, reduced vascular wall iron deposition and lipid peroxidation products (MDA, 4-HNE), and normalized aberrant expression of ferroptosis markers ACSL4, TFR1, GPX4 and FTH1. In vitro, it mitigated Erastin/Ang II-induced VSMC ferroptosis, improved mitochondrial structure and function by enhancing oxygen consumption rate (OCR), restoring membrane potential, reducing reactive oxygen species (ROS), and boosting mitophagy via upregulating HIF-1\u03b1 and mitophagy markers (PINK1, Parkin). The HIF-1\u03b1 inhibitor KC7F2 and siHIF-1\u03b1 reversed these effects. Taken together, our findings demonstrate that ROX protects against TAD by promoting HIF-1\u03b1 expression to enhance mitophagy and inhibit VSMC ferroptosis, offering potential clinical implications for TAD prevention and treatment.
PMID:42201682 | DOI:10.1096/fj.202600149R
Am J Transl Res. 2026 Apr 25;18(4):3479-3491. doi: 10.62347/KSVK9192. eCollection 2026.
ABSTRACT
OBJECTIVE: Aortic dissection (AD) represents a life-threatening vascular disorder characterized by abnormal vascular smooth muscle cell (VSMC) behavior and extracellular matrix remodeling. Growth differentiation factor 15 (GDF15) is a stress-related cytokine associated with the pathogenesis of cardiovascular diseases, but its exact role in AD remains to be elucidated.
METHODS: Human aortic smooth muscle cells (HASMCs) were incubated with angiotensin II (Ang II) to simulate an in vitro pathological tension environment. Gain- and loss-of-function experiments were carried out to investigate the functional role of GDF15 in regulating cell growth, migration, phenotypic transformation, and inflammatory reaction. The involvement of the ERK/protein kinase B (Akt) pathway was studied using a ERK inhibitor. Clinical significance was analyzed by detecting the plasma levels of GDF15 and matrix metalloproteinases (MMPs) in AD patients and healthy controls.
RESULTS: Ang II upregulated GDF15 expression in HASMCs in a dose- and time-dependent manner. GDF15 overexpression promoted HASMC proliferation, migration, and phenotypic switching from a contractile to a synthetic state, accompanied by increased expression of MMP-2 and MMP-9 and pro-inflammatory cytokines (TNF-\u03b1, IL-6, and MCP-1). GDF15 knockdown produced opposite effects. Mechanistically, GDF15 activated both ERK and Akt pathways; however, pharmacological inhibition experiments suggested that the pro-remodeling effects of GDF15 were primarily mediated through ERK signaling. Clinically, plasma concentrations of GDF15, MMP-2, and MMP-9 were significantly higher in AD patients compared with healthy controls.
CONCLUSIONS: GDF15 promotes aberrant remodeling of HASMCs by enhancing proliferation, migration, phenotypic transformation, and inflammatory responses via ERK-dependent signaling. Elevated plasma GDF15 levels in AD patients suggest that GDF15 can serve as a potential diagnostic biomarker and therapeutic target for AD.
PMID:42170476 | PMC:PMC13186724 | DOI:10.62347/KSVK9192
Am J Transl Res. 2026 Apr 25;18(4):3479-3491. doi: 10.62347/KSVK9192. eCollection 2026.
ABSTRACT
OBJECTIVE: Aortic dissection (AD) represents a life-threatening vascular disorder characterized by abnormal vascular smooth muscle cell (VSMC) behavior and extracellular matrix remodeling. Growth differentiation factor 15 (GDF15) is a stress-related cytokine associated with the pathogenesis of cardiovascular diseases, but its exact role in AD remains to be elucidated.
METHODS: Human aortic smooth muscle cells (HASMCs) were incubated with angiotensin II (Ang II) to simulate an in vitro pathological tension environment. Gain- and loss-of-function experiments were carried out to investigate the functional role of GDF15 in regulating cell growth, migration, phenotypic transformation, and inflammatory reaction. The involvement of the ERK/protein kinase B (Akt) pathway was studied using a ERK inhibitor. Clinical significance was analyzed by detecting the plasma levels of GDF15 and matrix metalloproteinases (MMPs) in AD patients and healthy controls.
RESULTS: Ang II upregulated GDF15 expression in HASMCs in a dose- and time-dependent manner. GDF15 overexpression promoted HASMC proliferation, migration, and phenotypic switching from a contractile to a synthetic state, accompanied by increased expression of MMP-2 and MMP-9 and pro-inflammatory cytokines (TNF-\u03b1, IL-6, and MCP-1). GDF15 knockdown produced opposite effects. Mechanistically, GDF15 activated both ERK and Akt pathways; however, pharmacological inhibition experiments suggested that the pro-remodeling effects of GDF15 were primarily mediated through ERK signaling. Clinically, plasma concentrations of GDF15, MMP-2, and MMP-9 were significantly higher in AD patients compared with healthy controls.
CONCLUSIONS: GDF15 promotes aberrant remodeling of HASMCs by enhancing proliferation, migration, phenotypic transformation, and inflammatory responses via ERK-dependent signaling. Elevated plasma GDF15 levels in AD patients suggest that GDF15 can serve as a potential diagnostic biomarker and therapeutic target for AD.
PMID:42170476 | PMC:PMC13186724 | DOI:10.62347/KSVK9192