自噬和线粒体自噬在ALDH2减轻内质网应激改善LPS所致心肌损伤中的作用及机制研究

Septic myocardial injury greatly increases the mortality of sepsis, as well as decreases the quality of lives of the survivors. We established the sepsis animal model by injecting LPS intraperitoneally and studied the effect of ALDH2 in this model by using ALDH2 transgenic mice. Our prior experiment showed that LPS-induced cardiac dysfunction, myocardial contractile dysfunction and calcium mishandling was significantly improved in ALDH2 overexpression mice compared to WT mice. Preliminary mechanism study showed that ER stress and autophagy levels in the heart tissue was obviously reduced in ALDH2 mice compared to WT mice after LPS injection, followed by the correspondingly changes in AMPK-mTOR signaling pathway. We also demonstrated that ER stress was the upstream mechanism of autopahgy, i.e. ALDH2 protected LPS-induced myocardial injury by inhibiting AMPK-mTOR-mediated autophagy through ameliorating ER stress. However, ① the detailed signaling information of the above-mentioned mechanism is still unknown; ②ER stress can trigger mitochondrial injury. Meanwhile, as a mitochondrial enzyme, ALDH2 has been reported to play important roles in regulating mitochondria function, mitochondria biogenesis and mitophagy. Therefore, we plan to investigate the mitochondria function and mitophagy level in this model, as well as to explore the effect of ALDH2 on it and the related mechanisms.

脓毒性心肌损伤极大地增加了脓毒症的病死率、降低了脓毒症存活患者的生活质量。本项目组前期使用LPS动物模型模拟脓毒性心肌损伤并研究了乙醛脱氢酶2（ALDH2）的作用，结果显示ALDH2过表达小鼠较野生型小鼠显著改善了LPS导致的心脏功能降低、心肌收缩舒张功能损伤及钙离子处理失调。初步机制研究表明，ALDH2过表达减轻LPS引起的内质网应激、过度自噬，同时伴随AMPK-mTOR通路蛋白表达的相应改变，体外实验进一步证明内质网应激是自噬的上游机制，即ALDH2通过减轻内质网应激抑制AMPK-mTOR介导的过度自噬而对LPS心肌损伤起到保护作用。然而①上述机制的完整信号通路尚未完全明了；②内质网应激可引起线粒体损伤，ALDH2作为线粒体酶，越来越多的证据表明其在调节线粒体功能、线粒体新生、线粒体自噬中有重要作用，本项目组拟进一步研究此模型线粒体自噬的改变，并探讨ALDH2对其发挥的作用及机制。

脓毒症心肌损伤显著增加脓毒症的病死率，加重国民经济和健康负担。本项目针对ALDH2在脓毒症心肌损伤中的作用及机制开展系列研究，发现乙醛脱氢酶2（ALDH2）对内毒素引起的心脏射血分数降低、心肌收缩功能减弱、心肌钙内流紊乱具有明显改善作用，ALDH2通过抑制内毒素诱导的内质网应激、介导CaMKKβ/AMPK/mTOR通路、抑制细胞内体形成，调节自噬和线粒体自噬等发挥心肌保护功能。研究成果说明ALDH2有望成为脓毒症心肌损伤的治疗新靶点。