ALDH2对高血糖所致心肌损伤保护作用的新机制：GSK3β/ULK1信号通路介导的自噬

Diabetic cardiomyopathy is one of the most serious complication of diabetes in cardiovascular system. Hyperglycemia has been shown to plan a pivotal role in diabetic cardiomyopathy. It was reported that hyperglycemia induced cardiac injury was associated with dysregulation of autophagy. Ample evidence from our laboratory has revealed a rather singular role for ALDH2 in cardioprotection against ischemic injury, arrhythmias and alcoholism. Recent evidence from our group has revealed a pivotal role for the downregulation of autophagy and mitochondrial, apoptotic and myocardial contractile anomalites as well as changes in the phosphorylation of Akt in ALDH2, in cardioprotection against hyperglycemia induced cardiac injury. However, the mechanism and downstream molecule of ALDH2 in myopathic anomalies and autophagy associated with diabetes mellitus have not been elucidated. The purpose of this project is to evalute if the protective roll of ALDH2 in hyperglycemia induced cardiac is associated with restore of autophagy and protection of mitochondrial anomaly through GSK3β/ULK1?pathway. to find a new mechanism?for ALDH2 protection in diabetic cardiomyopathy.? In summary, our present study will reveal a role of ALDH2 in the protection against diabetic cardiomyopathy, possibly via an GSK3β/ULK1-mediated preservation of cell survival and mitochondrial integrity. Our research indicates not only a role of ALDH2 in the prevalence of diabetic cardiomyopathy but also some therapeutic promise for ALDH2 in the management of diabetic complications.

糖尿病心肌病是最严重的糖尿病并发症且机制不明。高血糖是导致糖尿病心肌损伤的主要原因之一。最新文献表明高血糖导致的心肌损伤与自噬水平下调有关。我们最近发表的研究表明ALDH2对多种心肌损伤的保护作用与调节自噬水平，保护线粒体结构、功能密切相关。前期工作表明ALDH2可显著改善1型糖尿病小鼠心肌收缩舒张功能。然而ALDH2是否通过自噬实现其保护作用及其可能的下游分子及调控机制尚不完全清楚。本课题拟在此基础上，深入研究ALDH2对高血糖所致的心肌损伤保护作用的机制，揭示ALDH2是否通过GSK3β/ULK1信号通路，抑制自噬，保护线粒体功能及完整性，实现对高血糖导致的心肌损伤的保护作用，为ALDH2作为糖尿病性心肌病的治疗新靶点提供理论依据。本研究可进一步拓展人们对ALDH2糖尿病心肌保护作用的分子调控机制的认识，帮助寻找切实有效的治疗靶点，具有重要的理论意义和临床意义。

本项目严格按照项目计划书执行，通过本项目的研究获得如下结果：1、ALDH2可显著改善糖尿病小鼠心脏整体及单个心肌细胞的功能，证实了ALDH2对高血糖心肌损伤的保护作用与自噬的激活密切相关。抑制自噬可部分抵消ALDH2的保护作用，证实ALDH2通过激活自噬保护糖尿病心肌损伤；2、阐明ALDH2通过激活GSK3β/ULK1信号通路调节的自噬及其继发性线粒体保护，是其心肌保护作用的重要机制，ULK1的磷酸化修饰在其中起核心调节作用。本项目明确ALDH2的心肌保护作用机制提供了理论依据，同时为糖尿病心肌病的治疗提供了可能的干预靶点。在项目资助下，共发表SCI论文10篇，其中8篇影响因子大于5分，中文核心期刊3篇。项目负责人于2016年获得优秀青年基金资助，并于2016年获得教育部青年长江学者，2017年获得东方新星奖及中源协和生命医学奖，主要成果第一完成人获得陕西省科学技术奖二等奖1项。项目负责人多次在国内重要会议上进行大会发言或作为大会主持。项目组成员通力合作，逐步建立起糖尿病心肌病研究的小团队，项目共培养硕士研究生4名，其中2人次在国内大会交流。