SUMO化修饰活化转录因子6α在心肌病理性重构中的作用和机制研究

心肌病理性重构是心功能不全发生重要的病理生理过程。氧化应激所致心肌细胞凋亡参与心肌病理性重构。在青年基金资助下我们发现：慢性缺氧时活化转录因子6α (ATF6α)持续活化，上调氧化还原蛋白质表达，促进心肌细胞缺氧适应；ATF6α持续活化也能减轻长期超负荷所致心功能损伤。但在心肌病理性重构过程中，ATF6α表达水平逐渐降低，其调控机制尚不清楚。进一步研究发现ATF6α 能被SUMO化修饰，且心肌重构过程中其SUMO化水平显著降低。推测：SUMO-1通过SUMO化修饰ATF6α，增强ATF6α稳定性，减轻心肌病理性重构。基于此，我们拟采用主动脉缩窄建立小鼠心肌病理性重构模型，在体研究SUMO化修饰对ATF6α稳定性和活性的影响；采用WB、免疫共沉淀等在分子水平研究SUMO化修饰对ATF6α稳定性调控的分子机制。通过阐明ATF6α稳定性调控的机制，期望为逆转心肌病理性重构提供新靶点。

Myocardial pathological remodeling is an important pathophysiological process during cardiac dysfunction. Oxidative stress participates in this remodeling, but the regulatory mechanism is unclear. Our preliminary study found: chronic hypoxia-activated transcription factor 6α (ATF6α) sustained activation raised the redox protein expression, to promote myocardial hypoxia adaptation; ATF6α expression and its sumoylation were significantly decreased under some strong stimulations such as overload, and the specific ATF6α sustained activation in myocardial cells could delay the myocardial remodeling process. We speculate that: SUMO-1 regulates ATF6α stability by promoting its SUMO modification, and then reduce myocardial pathological remodeling. Based on this, this project intends to establish a mouse model of myocardial pathological remodeling by trans-aortic contruction, and use adeno-associated virus vectors for enhancing or alleviating the ATF6α SUMO modification in vivo, in order to study the regulation of ATF6α stability and activity and the inhibitory effect of myocardial pathological remodeling by SUMO modification. Also we plan to clarify the molecular mechanism of SUMO modification regulating ATF6α stability and transcriptional activity by immunofluorescence, western blot, and immune co-precipitation. The findings will be expected to clarify the mechanisms of ATF6α stability regulation.