血管平滑肌
肌钙蛋白
血管紧张素II
血清反应因子
细胞生物学
生物
转录因子
表型
基因沉默
内分泌学
基因
生物化学
平滑肌
血压
作者
Guangming Fang,Yuan Tian,Shan Huang,Xiaoping Zhang,Yan Liu,Yulin Li,Jie Du,Shan Gao
标识
DOI:10.1016/j.jbc.2024.107260
摘要
Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face. Progressive loss of the contractile apparatus in vascular smooth muscle cells (VSMCs) is a major event in TAD. Exploring the endogenous regulators essential for the contractile phenotype of VSMCs may aid the development of strategies to prevent TAD. Krüppel-like factor 15 (KLF15) overexpression was reported to inhibit TAD formation; however, the mechanisms by which KLF15 prevents TAD formation and whether KLF15 regulates the contractile phenotype of VSMCs in TAD are not well understood. Therefore, we investigated these unknown aspects of KLF15 function. We found that KLF15 expression was reduced in human TAD samples and β-aminopropionitrile monofumarate (BAPN)-induced TAD mouse model. Klf15KO mice are susceptible to both BAPN- and angiotensin II (Ang II)- induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix (ECM) degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor (SRF) coactivator that drives contractile gene expression. KLF15 silencing represses the MRTFB-induced activation of contractile genes in VSMCs. Thus, KLF15 cooperates with MRTFB to promote the expression of contractile genes in VSMCs and its dysfunction may exacerbate TAD. These findings indicate that KLF15 may be a novel therapeutic target for the treatment of TAD.
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