ALDH2调控线粒体网络发挥心肌缺血-再灌注损伤保护作用的机制研究

Aldehyde dehydrogenase 2(ALDH2) is a mitochondrial matrix enzyme that plays a crucial role in protecting heart against ischemia-reperfusion injury. Mitochondrial network is important for normal heart function. Mitochondrial fission occurred following myocardial ischemia-reperfusion and inhibition of fission reduced cardiac death. Our preliminary study showed that ALDH2 overexpression significantly reduced the percentage of cardiac cells containing fragmented mitochondria, as well as apotosis induced by ischemia-reperfusion injury. It is unknown so far whether the cardioprotection of ALDH2 invoves in regulating mitochondrial network. This research will use advanced techeniques (ALDH2 overexpression, ALDH2 silence, enhancing or inhibiting ALDH2 activity, ALDH2 transgenic mice and ALDH2 knockout mice in combination with blocking target molecules) to investigate the effect of ALDH2 on regulating mitochondrial network during myocardial ischemia-reperfusion and possible mechanisms. Furthermore, we will investigate the cardioprotective mechanisms mediated by ALDH2 in terms of mitochondrial network, mitochondrial autophagy and cellular apotosis. This research will contribute to reveal the novel molecular mechanisms for the cardioprotective effect of ALDH2 against ischemia-reperfusion injury, providing new therapeutic stratagy for cardioprotection.

乙醛脱氢酶2（ALDH2）是位于线粒体基质内的酶，具有重要的心肌保护作用。心肌缺血-再灌注过程中线粒体网络平衡破坏，线粒体分裂增加形成大量片段化的线粒体；而抑制线粒体分裂则减少心肌细胞死亡。我们前期研究发现心肌细胞过表达ALDH2可显著减少缺血-再灌注导致的片段化线粒体的形成以及细胞凋亡。ALDH2是否通过调控线粒体网络进而发挥心肌保护作用，目前尚无研究报道。本课题将采用体外（ALDH2过表达、ALDH2 基因沉默、提高或抑制ALDH2酶活性）和体内（ALDH2过表达转基因和ALDH2敲基因小鼠）相结合以及干预关键靶点的研究策略，探讨ALDH2对缺血-再灌注心肌线粒体网络的调控作用及机制，并从线粒体网络、线粒体自噬、细胞凋亡层面探讨ALDH2发挥心肌保护作用的机制。本项目将从新的视角阐明ALDH2对缺血-再灌注心肌发挥保护作用的内在分子机制，为以该酶为靶点的心肌保护策略提供新思路和方法。

乙醛脱氢酶2（ALDH2）是位于线粒体基质内的酶，具有重要的心肌保护作用。既往研究发现心肌缺血-再灌注过程中线粒体网络平衡破坏，线粒体分裂增加形成大量片段化的线粒体；而抑制线粒体分裂则减少心肌细胞死亡。我们前期研究发现心肌细胞过表达ALDH2可显著减少细胞凋亡的基础上，继续探讨ALDH2是否通过调控线粒体网络进而发挥心肌保护作用。本课题采用体外（ALDH2过表达、提高ALDH2酶活性）和体内（ALDH2过表达转基因和ALDH2敲基因小鼠）相结合以及干预关键靶点的研究策略，发现ALDH2抑制缺血-再灌注导致的线粒体碎片化，并通过抑制线粒体碎片化减少缺氧导致的细胞凋亡。本项目从新的视角阐明了ALDH2对缺血-再灌注心肌发挥保护作用的内在分子机制，为以该酶为靶点的心肌保护策略提供新思路和方法。