线粒体自噬在腺苷A2B受体活化诱导心肌再灌注保护中的作用及机制研究

心肌缺血/再灌注损伤是临床常见的病理过程，严重危害心肌梗死患者的生存和预后。线粒体氧化应激损伤是引起心肌缺血/再灌注损伤的重要原因。研究表明腺苷A2B受体活化减轻再灌注早期的线粒体氧化应激损伤，保护心肌。但随再灌时间延长，腺苷A2B受体活化对心肌的保护作用减弱，其原因尚未阐明。人们普遍认为线粒体自噬通过清除损伤线粒体，来减轻心肌再灌注损伤。但我们的前期研究发现腺苷A2B受体活化抑制线粒体自噬，提示这可能是腺苷A2B受体活化保护心肌的一个负性因素。本课题将探讨线粒体自噬在腺苷A2B受体活化诱导心肌再灌注保护中的作用及机制。为此，我们将利用生理学、药理学、分子生物学和蛋白质组学等方法验证如下假设：1）上调线粒体自噬增强腺苷A2B受体活化诱导的心肌再灌注保护作用；2）腺苷A2B受体活化，激活线粒体Src酪氨酸激酶，调控线粒体自噬受体，抑制线粒体自噬；3）线粒体膜腺苷A2B受体活化抑制线粒体自噬。

Myocardial ischemia/reperfusion injury is a common pathological process, which seriously affects the survival and prognosis of patients with myocardial infarction. Mitochondrial oxidative stress is regarded to be the chief cause of myocardial ischemia/reperfusion injury. Previous study has demonstrated that activation of adenosine A2B receptors prevents myocardial damage by decreasing mitochondrial oxidative stress at early reperfusion. However, the protective effect of adenosine A2B receptor activation decreases with time and the mechanism is not clearly underlined. It is generally believed that mitophagy prevents myocardial reperfusion injury by removing the damaged mitochondria. But our previous study has demonstrated that mitophagy is inhibited by adenosine A2B receptor activation which may be a key contributor to lessen the protective effects of adenosine A2B receptor activation. The overall objective of this project is to investigate the effects and mechanisms of mitophagy on adenosine A2B receptor activation-induced protection against myocardial reperfusion injury. This project will test the hypotheses that: 1) Mitophagy up-regulation increases the cardioprotective effect of adenosine A2B receptor activation during reperfusion; 2) The adenosine A2B receptor activation suppresses mitophagy by regulating the mitophagy receptors via Src tyrosine kinase; 3) The activation of mitochondrial adenosine A2B receptors could inhibit mitophagy.