Brg1调控血管内皮细胞稳态的机制及其在心肌肥大中的作用研究

Vascular endothelium plays essential roles guarding the physiological integrity of the vasculature. Confronted with a range of stress insults, vascular endothelial cells adapt a malcompensated phenotype characterized by the disruption of vascular barriers, unbalanced synthesis of vasoactive substances, and increased recruitment of circulating leukocytes with ensuing chronic inflammation, all of which contribute to the loss of vascular homeostasis and the development of cardiovascular disease. It remains obscure how these processes are regulated by the epigenetic machinery. Brahma related gene 1 (Brg1) is the core components of the mammalian chromatin remodeling complex. Brg1 is required for the organogenesis of cardiovascular system by altering the chromatin structure. Recently, we have found that Brg1 can be activated by a number of stress cues in vascular endothelial cells to participate in the transactivation of adhesion molecules, endothelin, and pro-inflammatory mediators. Endothelial-specific knockdown of Brg1 alleviates the pathogenesis of atherosclerosis and hypoxic induced pulmonary hypertension in mice. Building on these preliminary studies, we plan to perform genome wide analysis of endothelial-specific transcription by Brg1. Our specific aims are 1) to identify the transcriptome under the influence by Brg1, 2) to characterize the crosstalk between Brg1 and histone modifications, and 3) to address the pathophysiological relevance of endothelial Brg1. We hope to provide a common epigenetic link to the disruption of vascular homeostasis and novel targets for the development of interventional strategies against cardiovascular disease.

血管内皮在维持血管稳态过程中发挥不可或缺的作用。在体内外各种应激因素的刺激下，血管内皮细胞生理功能被破坏，这一过程是导致血管稳态失衡继而导致心血管疾病发生发展的关键，但其中的表观遗传调控机制尚未阐明。Brg1是细胞中染色质重构复合物的核心成分，通过改变染色质结构从而在哺乳动物心血管系统发育中发挥重要作用。我们前期的工作证实，Brg1在血管内皮细胞中被多种应激因素激活，并参与血管黏附分子、内皮素、炎症介质等基因的转录激活。血管内皮细胞中敲减Brg1后，小鼠罹患动脉粥样硬化与肺动脉高压程度明显减轻。在此基础上，我们拟进一步从转录组/表观遗传组水平分析Brg1如何在应激因素作用下改变内皮细胞转录谱，并如何引起病理性心肌肥大。通过这一研究，我们希望阐明调控血管稳态失衡的共有表观遗传学机制，从而为心血管疾病防治调控新靶点。

血管内皮在维持血管稳态过程中发挥不可或缺的作用。在体内外各种应激因素的刺激下，血管内皮细胞生理功能被破坏，这一过程是导致血管稳态失衡继而导致心血管疾病发生发展的关键，但其中的表观遗传调控机制尚未阐明。Brg1是细胞中染色质重构复合物的核心成分，通过改变染色质结构从而在哺乳动物心血管系统发育中发挥重要作用。本项目拟研究Brg1如何在应激因素作用下改变内皮细胞转录谱，并如何引起心血管疾病的发生发展。在本项目的资助下，近三年内主要取得了以下成果：（1）在血管紧张素（Ang II）诱导的心肌肥大模型中，内皮特异BRG1敲除（eCKO）小鼠心肌肥大程度较野生型小鼠明显减轻，同时血液中ET-1水平亦明显下调。BRG1与组蛋白甲基转移酶ASH2/WDR5的协同对话，共同激活ET-1基因表达，进而作用于心肌细胞引起肥大。（2）在CaCl2诱导的腹主动脉瘤模型中，eCKO小鼠相较野生型小鼠成瘤几率下降，动脉直径变小，MMP9/2表达及活性均有所下降。eCKO小鼠血管炎症水平下调，巨噬细胞招募减少。在体外培养的血管内皮细胞中，BRG1干扰RNA显著下调巨噬细胞集落刺激因子（CSF1）的表达。机制研究发现，BRG1与组蛋白修饰酶共同作用激活CSF1转录，从而增强巨噬细胞招募。（3）在缺血再灌注损伤模型中，eCKO小鼠相较野生型小鼠心肌梗死面积显著减少，心功能水平下降有所削弱。心肌中ROS水平由于BRG1缺失而降低，可能机制是BRG1通过激活NADPH氧化酶基因的转录从而促进心肌细胞凋亡。在研期间发表标注资助号的研究论文15篇；其中第一标注论文10篇。