SIRT1下调致Akt-p53信号通路失调增加糖尿病心肌缺血易损性及其机制

Diabetic hearts are more sensitive to ischemic injury than non-diabetic hearts. However, the mechanisms are unclear. Myocardial ischemia/reperfusion (MI/R) injury has been shown to be associated with the activation of Akt-p53 signaling pathway. Pro-apoptotic p53 is known to be inhibited by Akt that promotes cell survival. We recently found that diabetic I/R hearts showed blocked activation of Akt and enhanced activity of p53, suggesting dysregulated Akt-p53 signaling pathway may participate in increased ischemic vulnerability of diabetic heart. Our further study found that diabetic hearts exhibited reduced deacetylase SIRT1 expression and increased Akt/p53 acetylation, which may be one important mechanism that account for dysregulated Akt-p53 signaling pathway. Based on these previous researches, we aimed to determine whether down-regulated SIRT1 led to increased Akt/p53 acetylation and then disturbed Akt-p53 signaling pathway, which made the diabetic hearts more sensitive to I/R injury. The present study was designed to clarify the role of SIRT1-deacetylated Akt-p53 signaling pathway in the diabetic MI/R injury. This research is hoped to further understand the pathogenesis of increased ischemic vulnerability in diabetic heart and provide novel possible targets for the treatment of ischemic heart disease in diabetic patients.

糖尿病心肌缺血易损性增加，然而其机制尚不清楚。前期研究显示，心肌缺血后Akt-p53信号通路被激活，促生存的Akt可在一定程度上抑制p53的促凋亡效应，而我们新近的预实验发现，糖尿病心肌缺血后Akt激活受阻，p53活性增强，提示Akt-p53信号通路失调与糖尿病心肌缺血易损性增加有关。进一步的研究发现，糖尿病心肌去乙酰化酶SIRT1表达下调，Akt与p53乙酰化水平增加，可能是Akt-p53信号通路失调的重要机制。本课题拟在前期研究基础上，探讨糖尿病心肌SIRT1下调可否增加Akt与p53乙酰化水平，使得心肌缺血后Akt激活受阻，p53活性增强，导致Akt-p53信号通路失调，从而加重缺血损伤。本研究期望阐明SIRT1去乙酰化调节Akt-p53信号通路在糖尿病心肌缺血损伤中的作用，为深入认识糖尿病心肌缺血损伤机理提供实验依据，并为糖尿病性心脏病的防治提供新策略和新思路。

糖尿病心肌对缺血的耐受力降低，缺血易损性增加。包括缺血后处理在内的一些干预措施对糖尿病心肌的保护效果受损。在本项目资助下我们发现：糖尿病心肌缺血再灌注损伤加重，Akt激活受阻，p53活性变化不明显，缺血后处理不能有效激活Akt信号通路；腺病毒转染上调糖尿病心肌SIRT1后，乙酰化Akt表达减少，缺血再灌注损伤减轻，缺血后处理可激活Akt信号通路保护心肌；在SIRT1敲除心肌，乙酰化Akt表达增加，缺血再灌注损伤加重，缺血后处理不能有效激活Akt信号通路保护心肌；高糖环境上调野生型而非突变型SIRT1可恢复缺氧后处理激活Akt信号通路保护心肌细胞的效应，去乙酰化修饰Akt可增加其减轻心肌细胞缺氧损伤的效应，乙酰化修饰Akt可阻断其保护效应。本研究阐明了SIRT1在糖尿病心肌缺血损伤加重和后处理失效中的作用及机制，提示临床上激活SIRT1信号分子对糖尿病相关的心脏疾病进行干预可能具有积极意义。