Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection - 22/03/24
Abstract |
Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the β-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | HDAC9 promotes contractile-to-synthetic phenotypic transformation of VSMCs. |
• | HDAC9 regulates proliferation, apoptosis and cell cycle of VSMCs. |
• | TMP195 treatment suppressed the development and progression of AAD in mice. |
• | Inhibiting HDAC9 expression may serve as a potential strategy for AAD treatment. |
Abbreviations : VSMCs, AAD, TAD, AAS, IMH, PAU, ECM, MMPs, HDACs, HASMCs, MVSMCs, IGFBP3, SOD2.
Keywords : Aortic aneurysm/dissection, Vascular smooth muscle cells, Phenotypic transformation, Histone deacetylase 9
Plan
Vol 173
Article 116396- avril 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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