BAF60a Deficiency in Vascular Smooth Muscle Cells Prevents Abdominal Aortic Aneurysm by Reducing Inflammation and Extracellular Matrix Degradation.
BAF60a Deficiency in Vascular Smooth Muscle Cells Prevents Abdominal Aortic Aneurysm by Reducing Inflammation and Extracellular Matrix Degradation.
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DOI：
10.1161/atvbaha.120.314955
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
Chang Z;Zhao G;Zhao Y;Lu H;Xiong W;Liang W;Sun J;Wang H;Zhu T;Rom O;Guo Y;Fan Y;Chang L;Yang B;Garcia-Barrio MT;Lin JD;Chen YE;Zhang J
目前，还没有批准的治疗腹主动脉瘤（AAA）的药物，可能是由于对AAA发生和进展的主要分子机制的了解有限。BAF60a是开关/糖不可发酵（SWI/SNF）染色质重塑复合体的一个独特亚基，是一种新的代谢稳态调节剂，但其在血管系统和AAA发病机制中的功能尚不清楚。在本研究中，我们试图探讨血管平滑肌细胞（VSMC）特异性BAF60a在AAA形成中的作用及其潜在机制。BAF60a在人和实验性小鼠AAA病变中表达上调。体内研究表明，vsmc特异性敲除BAF60a可保护小鼠免受AngII-和弹性酶诱导的AAA形成，并显著抑制血管炎症、单核细胞浸润和弹性蛋白断裂。通过rna测序和通路分析，我们发现在培养的人主动脉平滑肌细胞（HASMCs）中，siRNA介导的BAF60a敲低显著下调炎症反应基因的表达，而腺病毒介导的BAF60a过表达显著上调炎症反应基因的表达。BAF60a通过将SWI/SNF复合物的催化亚基BRG1招募到NF-κB靶基因的启动子区域来调节VSMC炎症。此外，VSMC中BAF60a的缺失阻止了半胱氨酸蛋白酶组织蛋白酶S的上调，从而改善了AAA血管壁内细胞外基质（ECM）的降解。我们的研究表明，BAF60a需要招募SWI/SNF复合物，以促进VSMC炎症的表观遗传调控，这可能是预防和治疗AAA的潜在治疗靶点。
Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a, a unique subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)-specific BAF60a in AAA formation. BAF60a is upregulated in human and experimental murine AAA lesions. In vivo studies revealed that VSMC-specific knockout of BAF60a protected mice from both AngII- and elastase-induced AAA formation with significant suppression of vascular inflammation, monocyte infiltration, and elastin fragmentation. Through RNA-sequencing and pathway analysis, we found that the expression of inflammatory response genes in cultured human aortic smooth muscle cells (HASMCs) was significantly downregulated by siRNA mediated BAF60a knockdown while upregulated upon adenovirus mediated BAF60a overexpression. BAF60a regulates VSMC inflammation by recruiting BRG1, a catalytic subunit of the SWI/SNF complex, to the promoter region of NF-κB target genes. Furthermore, loss of BAF60a in VSMCs prevented the upregulation of the proteolytic enzyme cysteine protease cathepsin S, thus ameliorating extracellular matrix (ECM) degradation within the vascular wall in AAA. Our study demonstrated that BAF60a is required to recruit the SWI/SNF complex in order to facilitate the epigenetic regulation of VSMC inflammation, which may serve as a potential therapeutic target in preventing and treating AAA.