SIRT6对自噬的调控及其与心肌细胞肥大的关系研究

项目名称： SIRT6对自噬的调控及其与心肌细胞肥大的关系研究

项目编号： No.81200096

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 叶建涛

作者单位： 中山大学

项目金额： 23万元

中文摘要： 心肌肥大是心血管疾病的独立危险因素，与表观遗传调控关系密切。我们前期发现，Ⅲ类组蛋白去乙酰化酶Sirtuins家族的SIRT6亚型具有依赖于其去乙酰化酶活性的抗心肌肥大功能，但机制有待阐明。自噬是细胞内物质降解的主要途径之一，对保证细胞基本的能量需要、维持内环境稳定具重要意义。我们在异丙肾上腺素诱导乳鼠心肌细胞肥大模型中观察到自噬水平下降，并且发现在心肌细胞中过表达SIRT6可提高自噬水平，认为适度激活自噬可能有助于心肌肥大的防治，SIRT6抗心肌肥大作用可能与调节心肌细胞自噬有关。本课题拟在此基础上重点寻找与SIRT6直接作用或受其去乙酰化修饰的自噬相关基因编码蛋白，探讨SIRT6调控自噬与其去乙酰化酶活性的关系，并利用腺病毒载体心室壁注射技术，在大鼠心脏中特异性过表达SIRT6，研究SIRT6、自噬和心肌肥大之间的关系，分析SIRT6抗心肌肥大的分子机制及作为心肌肥大治疗靶点的可能性。

中文关键词： SIRT6；自噬；心肌肥大；分子机制；Akt/FoxO3通路

英文摘要： Cardiac hypertrophy, as a common independent risk factor for various cardiovascular diseases, has a close relationship with epigenetic regulation. The sirtuins (SIRT) family belongs to class III histone deacetylases (HDACs) and includes seven members. Previously, we have demonstrated that SIRT6 could protect cardiomyocytes from hypertrophic response, which was dependent on its deacetylase activity. However, the molecular mechanism underlying the anti-hypertrophic effect of SIRT6 remains to be clarified. It's known that autophagy is one of the main processes that allow for the degradation of proteins and organelles, and plays an important role in the maintenance of intracellular environment stabilization. Recent evidences have revealed that the autophagy of cardiomyocytes should be kept at an appropriate level to avoid cardiac malfunction. In cultured neonatal rat cardiomyocytes submitted to isoproterenol stimulation, we observed downregulation of autophagy accompanying with cellular hypertrophy Moreover, our experiments showed that overexpression of SIRT6 in cardiomyocytes could result in increased level of autophagy. It suggests that moderate activation of autophagy may be an effective way to prevent cardiac hypertrophy. Intrigued by these findings, we ask whether the anti-hypertrophic effect of SIRT6 can be at

英文关键词： SIRT6；autophagy；cardiac hypertrophy；molecular mechanism；Akt/FoxO3 pathway