Sirtuin蛋白家族在衰老心肌缺血/再灌注损伤易损性增加中的机制研究

项目名称： Sirtuin蛋白家族在衰老心肌缺血/再灌注损伤易损性增加中的机制研究

项目编号： No.81470410

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈迈

作者单位： 中国人民解放军第四军医大学

项目金额： 73万元

中文摘要： 衰老心肌对于缺血损伤的耐受性明显下降，其分子机制仍未探明。Sirtuin 蛋白家族中Type 1蛋白介导抗凋亡，而Type 2蛋白却可引发细胞程序性坏死，这两种蛋白信号如何在心肌中达到动态平衡是阐明心肌损伤机制所需解决的全新课题。我们发现AMPK-NAMPT-NAD+通路衰退可降低衰老心肌Sirtuin type 1蛋白活性；在低NAD+水平和type1蛋白活性受抑情况下，阻断type 2蛋白能减少衰老心肌梗死面积，故设想衰老心肌缺血易损性增加可能由Sirtuin type 1蛋白抗凋亡能力的减退和type 2蛋白的促坏死作用共同导致。本研究将在细胞、分子及动物水平全面探讨衰老心肌Sirtuin type 1蛋白活性减退与type 2蛋白诱发心肌坏死的关键调控机制，并通过对这两种蛋白的选择性基因干预，实现抗凋亡/抑坏死协同提高衰老心肌抗缺血损伤能力，为缺血性心脏病的治疗提供新的思路和方向。

中文关键词： 心肌细胞；衰老心肌；细胞凋亡；程序性坏死；缺血/再灌注损伤

英文摘要： The mechanism of aging-related vulnerability to myocardial ischemia reperfusion injury remains unclear. Type 1 protein of Sirtuin protein family (SIRT1) has been shown to inhibit myocardial apoptosis. In contrast, Type 2 protein of Sirtuin protein family (SIRT2) has been shown to trigger necroptosis. It is a new issue that how the SIRT1 induced cell survival coexist with the SIRT2 induced cell necroptosis in heart. Our previous studies found that ①AMPK-NAMPT-NAD+ pathway recession may reduce myocardial SIRT1 activity and impaire SIRT1's nucleocytoplasmic shutting in the senescent heart; ② A low level of NAD+ and decline in the activity of SIRT1 have been described in the senescent heart, specific blocking SIRT2 is still can effectively reduce the myocardial infarction. We hypothesize that impaired anti-apoptotic effect cause declined SIRT1 activation and SIRT2 induced necroptosis may jointly result in intolerance of the senescent heart to ischemic insults. Therefore, Transgenic mouse model and selective genetic intervention were utilized to examine the key regulatory mechanisms about impaired SIRT1 activation and SIRT2 induced necroptosis in the ischemic senescent heart. We also would investigate that synergistic inhibition the apotosis/necroptosis signaling cascade is a potential target for ameliorating the intolerance of aged heart to ischemic insults. The aim of the project is to enhance our mechanistic understanding of the relationship between myocardium survival and death during the aging process.

英文关键词： Myocytes;Aging heart;Apoptosis;Necroptosis;Ischemic/Reperfusion injury