Redd1激活细胞自噬与抗凋亡通路在心肌梗死中的双重保护作用

心肌梗死因持久而严重的缺血缺氧导致急性心肌坏死。作为机体的应激反应，抗细胞凋亡和自噬是两条重要的保护机制，但在心梗中的调控并不完全清楚。我们的前期研究表明Redd1通过增强自噬以抑制心肌肥厚从而保护心肌。作为低氧应答基因，Redd1在心肌梗死中的作用及调控机制尚无报道。预实验发现，缺氧的心肌细胞中Redd1明显促进抗凋亡蛋白Bcl-2的表达，抑制凋亡酶Caspase-3的活性，并同时上调自噬标志蛋白LC-3-II和自噬基因Atg7的表达，提示Redd1在心肌细胞中可能具有抗凋亡和诱导自噬的双重作用。在此基础上，本研究拟通过建立心肌梗死动物模型以及缺氧心肌细胞模型，利用腺病毒转染技术和敲除小鼠过表达和拮抗 Redd1，探讨Redd1是否通过激活Bcl-2介导的抗凋亡通路和Atg7介导的自噬通路从而双重保护心肌细胞，减少心梗面积，保护心功能，从而为心肌梗死的临床治疗提供新靶点和重要依据。

Myocardial infarction occurs when blood flow stops to part of the heart causing cardiac muscle injury. Anti-apoptosis and autophagy are two important protective events usually initiated by the body as stress reactions in response to adverse stimuli. However, their regulations during myocardial infarction are incompletely understood. We previously reported that Redd1 attenuated cardiac hypertrophy via enhancing autophagy. Whether Redd1, which is is sharply induced under the condition of hypoxia, exerts protective roles in myocardial infarction and its regulatory mechanism yet remain to be established. Recently, our preliminary results demonstrated that, in cardiomyocytes undergoing hypoxia, Redd1 not only markedly induced expression of anti-apoptotic protein Bcl-2 and inhibited activity of proapoptotic proteinase Caspase-3, but also increased production of autophagic marker LC-3-II and expression of important autophagy gene Atg7, suggesting that Redd1 is likely to exert both anti-apoptotic and autophagic effects on cardiomyocytes in response to hypoxia-induced stress reaction. Therefore, in the current project, based on establishment of the animal and cellular models mimicking myocardial infarction and employment of adenovirus transfection and knockout mice to introduce or antagonize Redd1 expression, we are aiming to further investigate whether Redd1 dually activates Bcl-2-mediated anti-apoptotic pathway and Atg7-mediated autophagic pathway, to exert protective roles in maintaining cardiomyocytes survival, decreasing necrosis area and preserving heart function. The current project would help to provide important evidence for identifying a novel therapeutic target for treatment of myocardial infarction.