ALDH2在心肌程序性坏死中的作用及机制研究

A significant breakthrough in cell death field is the discovery that necrosis can also be regulated (termed necroptosis) in recent decade. However, the investigation of necrosis signaling and endogenous cardioprotection is in the early stages. We have been focused on the cardioprotective mechanisms mediated by ALDH2 in terms of cellular apoptosis, et al. we keenly recognized that ALDH2 might paly an important role in the regulation of myocardial necroptosis. We studied the role of ALDH2 in ischemia/reperfusion- and cyclophosphamide-induced myocardial necroptosis, since acute myocardial infarction and cardiotoxicity of anti-cancer drugs are two important public problems currently. Our preliminary study showed that ALDH2 could significantly reduced myocardial necroptosis and formation of ox-CaMKII and reversed depolarization of the mitochondrial membrance potential(△Ψm) induced by either ischemia/reperfusion or cyclophosphamide. This research will use advanced techeniques in vivo and in vitro (ALDH2 overexpression in combination with blocking target molecules) to investigate the underlying mechanisms why ALDH2 inhibits the formation of ox-CaMKII and to demonstrate whether the cardioprotective mechanisms mediated by ALDH2 is through inhibition of ox-CaMKII formation, inhibition of mPTP opening and improvement of depolarization of the △Ψm. Additionally, we will investigate whether Alda-1(ALDH2 specific agonist) has the similar role in protecting myocardial necroptosis. This research will contribute to reveal the novel molecular mechanisms for the role of ALDH2 in myocardial necroptosis, which could be a potential therapeutic target for drug development.

心肌程序性坏死的发现是近10年来细胞坏死领域的重大突破，但目前对于心肌程序性坏死的信号通路知之甚少。课题组专注于乙醛脱氢酶2（ALDH2）心肌保护机制的研究，申请人敏锐地意识到ALDH2的心肌保护作用可能不仅是抗细胞凋亡，而是抗心肌程序性坏死。考虑到急性心肌梗死以及抗肿瘤药物的心肌毒性这两大社会公共问题，课题组优先探讨ALDH2对缺血/再灌注、环磷酰胺导致心肌坏死的作用。前期研究发现ALDH2改善缺血/再灌注、环磷酰胺导致的心肌坏死、减少ox-CaMKII的形成，改善线粒体功能。本课题拟在前期研究结果的基础上，采用体外和体内相结合以及干预关键靶点的策略，揭示AlDH2抑制CaMKII氧化的分子机制，阐明ALDH2是否通过抑制CaMKII氧化及mPTP开放，改善线粒体功能，减少心肌坏死；并探讨ALDH2激动剂Alda-1对心肌程序性坏死的作用及机制，为基于ALDH2为靶点的药物研发提供依据。

心肌缺血再灌注(MI/R)损伤限制了冠状再灌注治疗的效果。程序性坏死是MI/R损伤的重要调控因素。乙醛脱氢酶2(ALDH2)是多种醛类的代谢酶。4-羟基-2-壬烯醛(4-HNE)在MI/R损伤过程中大量增加。然而，4-HNE是否会导致细胞坏死仍然是未知的。本课题通过构建小鼠心肌缺血再灌注模型，证实了ALDH2通过代谢4-HNE抑制程序性坏死减轻MI/R损伤，进而通过细胞模型，研究4-HNE在MI/R损伤中发挥作用的机制，探明了4-HNE通过降低受体相互作用蛋白1(RIP1)的蛋白的降解加重MI/R损伤，为MI/R损伤的防治提供新的干预方法。