Brg1在心肌梗死电生理重构中的作用及其表观遗传学调控机制

Myocardial electrophysiological remodeling in myocardial infarction (MI) is the main cause of malignant arrhythmia and sudden cardiac death. In our preliminary study, Brg1 protein was increased significantly in MI, and cardiac-specific knockout Brg1 can decrease the frequency of arrhythmia in MI. Therefore we speculated that Brg 1 is an important regulator associated with arrhythmias in MI, but the detailed mechanisms have not been elucidated. CircRNAs is one kind of non-coding RNA with cyclic structure, which has been proved to be closely related to many heart diseases. In the preliminary study, we found that circRNA-27373 was significantly upregulated in infarcted tissues by microbarray screening, and its expression was positively correlated to Brg1. This project will employ molecular cloning, luciferase and electrophysiological techniques to verify: (1) the important role of Brg1 in myocardial electrophysiological remodeling after MI; (2) epigenetic regulatory mechanism of Brg1 inhibition of transcriptional activity and transcriptional extension in myocardial electrophysiological remodeling after MI; (3) whether circRNA-27373 is the upstream regulatory factor of Brg1 in MI. In this study, we will find a new target to inhibit cardiac arrhythmias in MI, and we will provide new insights into the treatment of cardiac arrhythmias in MI and the prevention of sudden cardiac death.

心肌梗死后心肌电生理重构是恶性心律失常、心源性猝死发生的主要原因。本项目前期研究发现染色质重组子Brg1在心肌梗死后表达增多，心脏特异性敲除Brg1，降低心肌梗死后心律失常发生率，推测Brg1参与心肌电生理重构但具体机制尚不明确。CircRNAs是一类环状结构的非编码RNA，已证实与多种心脏疾病发生密切相关。前期芯片筛选发现circRNA-27373在心肌梗死边缘区组织中显著上调，且其表达水平与Brg1表达呈正相关。本课题拟运用分子克隆、Luciferase及电生理学等技术(1) 揭示Brg1在心肌梗死电生理重构的重要作用；（2）揭示Brg1抑制转录活性和转录延伸的表观遗传调控心肌梗死电生理重构的机制；（3）验证circRNA-27373是心肌梗死时引起Brg1增高的上游调控因子。本研究将发现抑制心肌梗死后心律失常的新靶点，为临床防治心肌梗死后心律失常及心源性猝死的发生提供新思路。

心肌梗死后心肌电生理重构是恶性心律失常、心源性猝死发生的主要原因。本项目前期研究发现染色质重组子Brg1在心肌梗死后表达增多，心脏特异性敲除Brg1，降低心肌梗死后心律失常发生率，本课题运用分子克隆、Luciferase及电生理学等技术揭示Brg1在心肌梗死电生理重构的重要作用；进一步阐明了Brg1抑制转录活性和转录延伸的表观遗传调控心肌梗死电生理重构的机制。完成主要目标同时本项目还有新发现：Brg1对心肌细胞TRPM4通道具有正向调控作用；Brg1对心肌梗死后心肌纤维化具有促进作用；Brg1特异性抑制剂PFI3影响离体大鼠肠系膜血管张力，并对以上发生机制进行了深入探究，进一步阐明了染色质重组子Brg1对于心血管疾病发生发展的重要作用，为深入了解Brg1的表观遗传调控作用提供重要的理论依据。本课题相关研究结果共发表国内核心期刊论文3篇，另有2篇SCI文章已投稿。项目负责人参与获得黑龙江省高等教育教学成果特等奖1项，参编学术专著1部，项目资助下共培养博士研究生1名，硕士研究生6名，本科生1名，其中已毕业硕士研究生4名，毕业本科生1名。