心肌特异性敲除MEF2A对缺氧诱导的心肌细胞凋亡及再生的影响及机制研究

Acute myocardial infarction (AMI) is one of the major diseases threatening human health. Myocardial apotheosis and regeneration play an essential role in the development of AMI. Myocyte Enhancer Factor 2A (MEF2A) was firstly reported to be as an inherited marker for coronary artery disease. It has been reported the association between the MEF2A gene and myocardial infarction, which focus primarily on MEF2A gene mutational screening on patients with premature MI and controls. However, the precise influence of MEF2A on AMI pathogenesis has not yet been fully elucidated. Accumulated evidence suggests that MEF2A is implicated in the pathophysiological processes of mitochondrion injury and cardiogenesis. Mitochondrion injury causes myocardial apotheosis. Hence we speculate that MEF2A could improve AMI-induced cardiac structure and function disorder via suppressing myocardial apoptosis and stimulating regeneration. Hypoxia leads to the change of MEF2A expression and location. MEF2A plays an important role in the feedback loop of hypoxia→MAPK/PI3K-Akt →MEF2A →DUSP-6 →MAPK/PI3K-Akt. We will construct mice of myocardium conditional knock-out MEF2A, examine the role of MEF2A in vivo using a mice model of AMI. We will infect primary cardiomyocytes and cardiac stem cell in vitro with lent virus vector to knockdown and overexpression of MEF2A and BCI hydrochloride (inhibitor of DUSP-6), examine the effects of MEF2A on myocardial apoptosis and regeneration, and further explore the mechanism. The study provides a theoretical basis that MEF2A plays pivotal roles in the development of AMI, and MEF2A can be a potential target of diagnosis and therapy AMI.

心肌细胞凋亡和再生是决定急性心肌梗死（acute myocardial infarction, AMI）转归的重要因素。肌细胞增强因子2A(Myocyte Enhancer Factor 2A, MEF2A)与AMI的相关性研究只是关于基因扫描对比，未见对AMI发病机制影响的相关报道。文献及前期工作研究显示MEF2A在线粒体稳态维持及心脏发生中有重要作用，而线粒体稳态失衡可促心肌细胞凋亡。因此我们推测缺氧致MEF2A表达及定位变化，并通过缺氧→MAPK/PI3K-Akt→MEF2A→DUSP-6→MAPK/PI3K反馈环路参与心肌细胞凋亡及再生调节。在心肌特异性敲除Mef2a小鼠及原代心肌细胞缺氧模型上，采用细胞和分子生物学等手段，对MEF2A调节AMI后心肌细胞凋亡和再生的作用和机制进行研究。本项目意义在于明确MEF2A在AMI中的作用和调节机制，为发现潜在AMI诊治靶点提供理论依据。