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.

中文翻译：

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KLF15 通过与 MRTFB 相互作用维持血管平滑肌细胞的收缩表型并预防胸主动脉夹层


胸主动脉夹层（TAD）是一种高度危险的心血管疾病，由主动脉壁薄弱导致内表面突然撕裂引起。血管平滑肌细胞 (VSMC) 收缩器官的逐渐丧失是 TAD 的一个主要事件。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) 过度表达可抑制 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，我们研究了 KLF15 功能的这些未知方面。我们发现，在人类 TAD 样本和 β-氨基丙腈单富马酸盐诱导的 TAD 小鼠模型中，KLF15 表达降低。 Klf15KO 小鼠对 β-氨基丙腈单富马酸盐和血管紧张素 II 诱导的 TAD 敏感。 KLF15 缺乏会导致 VSMC 收缩力降低，并加剧血管炎症和细胞外基质降解。从机制上讲，KLF15 与心肌素相关转录因子 B (MRTFB) 相互作用，MRTFB 是一种有效的血清反应因子共激活剂，可驱动收缩基因表达。 KLF15 沉默抑制 MRTFB 诱导的 VSMC 收缩基因激活。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的新治疗靶点。