PDF(Pubmed)
Abstract：
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-induced TAD mouse model. Klf15KO mice are susceptible to both β-aminopropionitrile monofumarate- and angiotensin II-induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor 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.
摘要：
胸主动脉夹层（TAD）是由主动脉壁弱化引起的高度危险的心血管疾病，导致内部面部突然撕裂。血管平滑肌细胞（VSMC）中收缩装置的逐渐丧失是TAD中的主要事件。探索VSMC收缩表型所必需的内源性调节因子可能有助于制定预防TAD的策略。据报道，Krüppel样因子15（KLF15）过表达抑制TAD形成；然而，KLF15阻止TAD形成的机制以及KLF15是否调节TAD中VSMC的收缩表型尚不清楚.因此,我们调查了KLF15功能的这些未知方面。我们发现在人TAD样品和单富马酸β-氨基丙腈(BAPN)诱导的TAD小鼠模型中KLF15表达降低。Klf15KO小鼠对BAPN-和血管紧张素II(AngII)-诱导的TAD敏感。KLF15缺乏导致VSMC收缩性降低并加剧血管炎症和细胞外基质(ECM)降解。机械上,KLF15与心肌相关转录因子B（MRTFB）相互作用，驱动收缩基因表达的有效血清反应因子（SRF）共激活因子。KLF15沉默抑制MRTFB诱导的VSMC中收缩基因的激活。因此，KLF15与MRTFB协同促进VSMC中收缩基因的表达，其功能障碍可能会加剧TAD。这些发现表明KLF15可能是治疗TAD的新治疗靶标。
