近年来心肌肥大与表观遗传调控的关系日益受到重视。我们前期研究表明，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作用，但具体机制尚待阐明。由于SIRT6酶活性受NAD水平影响，因此我们设想通过抑制NAD消耗可上调SIRT6活性并对抗心肌肥大。PARPs是细胞内NAD的主要消耗酶。在预实验中，我们发现抑制PARP-2可改善AngⅡ诱导的心肌细胞肥大，并激活SIRT6。本课题拟在此基础上利用腺病毒载体心室壁注射技术，在大鼠心脏中沉默PARP-2，进一步明确抑制PARP-2在整体动物中的抗心肌肥大作用，并采用免疫共沉淀、凝胶电泳迁移率变动分析、染色质免疫沉淀和双荧光素酶报告基因等方法，研究PARP-2调控SIRT6的分子机制，初步探讨通过调控PARP-2影响SIRT6进而干预心肌肥大的可能性，为确立SIRT6作为心肌肥大治疗的新靶点提供理论依据。

The relation between epigenetic regulation and cardiac hypertrophy has attracted much attention during recent years. Previously, we have demonstrated that SIRT6, a family member of class III histone deacetylases (HDACs), could protect cardiomyocytes from hypertrophic responses, which was dependent on its deacetylase activity. However, the mechanism underlying the anti-hypertrophic effect of SIRT6 remains to be clarified. Intrigued by the fact that the activity of SIRT6 is susceptible to intracellular NAD level, we speculate that it may be possible to activate SIRT6 and subsequently inhibit cardiac hypertrophy by reducing NAD consumption. PARPs are the major cellular NAD consumers. In cultured neonatal rat cardiomyocytes submitted to angiotensinⅡ(AngⅡ) stimulation, we observed a significant upregulation of PARP-2 expression accompanying with cellular hypertrophy. Moreover, our experiments showed that PARP-2 deletion protected cardiomyocytes from hypertrophy. This study is aimed to elucidate the role of PARP-2 in cardiac hypertrophy by cardiac-specific PARP-2 knockdown through direct injection of adenovirus vector into rat left ventricular wall. We will also investigate the molecular mechanisms of PARP-2 on SIRT6 regulation and the feasibility of inhibiting cardiac hypertrophy via PARP-2/SIRT6 pathway by using co-immunoprecipitation assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and dual luciferase reporter assay. Our research will provide a further insight into the mechanism underlying the anti-hypertrophic effect of SIRT6 and support the novel therapeutic strategy against cardiac hypertrophy by targeting SIRT6.