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

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.

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。

阐明心肌梗死过程中机体的应激反应和外源性干预的调控作用，寻找心肌梗死的内源性和外源性保护因子，从而为急性心衰寻找可能的分子诊断标志物及有效治疗靶点具有重要意义。本项目主要发现了内源性应激保护因子Redd1调控心肌细胞抗凋亡和诱导细胞自噬的生物学作用，阐明了Redd1同时激活NF-κB 和FOXO3a的转录活性，从而上调抗凋亡蛋白和促自噬基因表达的调控机制。此外，我们也发现了另一内源性保护因子CCN1联合NT-proBNP能有效提高急性心力衰竭患者的预后评估功能，发现了在水果和蔬菜中富含的天然化学物质Fisetin和Lycopene具有通过阻抑过度氧化应激抑制压力过载引起的心肌肥厚等生物学作用。本项目发掘和探索了内源性和外源性保护因子在心肌梗死、心肌肥厚及心力衰竭中保护心功能的生物学作用与分子机制，为心血管疾病尤其是心力衰竭的预防、临床诊断和预后判断提供创新性的分子标志物。

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