SIRT1介导姜黄素后处理抗心肌缺血再灌注损伤的机制研究

缺血再灌注损伤(I/RI)是缺血性心脏病预后不良的主要原因之一，药物后处理是对抗心肌I/RI的重要策略。SIRT1是心脏保护方面最基本的内源性抗凋亡转录因子之一，激活SIRT1通过FOXO1-抗凋亡途径对抗心肌I/RI；SIRT1与JAK2/STAT3通路相互调节共同介导多种组织器官病理生理过程。我们首先证实：姜黄素后处理抗心肌I/RI作用依赖于JAK2/STAT3通路激活，并伴随SIRT1表达上调，但具体机制不明。综上我们推测：姜黄素后处理激活SIRT1并与JAK2/STAT3通路相互作用，最终通过FOXO1-抗凋亡途径发挥抗心肌I/RI作用。本项目采用SIRT1基因敲除小鼠、在体/离体心脏、心肌细胞模型，应用Western blot、siRNA干扰等方法，阐明SIRT1和JAK2/STAT3通路介导姜黄素抗心肌I/RI的机制，为研发以姜黄素为基础的药物后处理心肌保护方法提供理论依据。

Ischemia-reperfusion injury (I/RI) is one of the main reasons for poor clinical treatment of ischemic heart disease. Pharmacological post-conditioning is a crucial strategy to fight against I/RI. SIRT1 is one of the basic endogenous anti-apoptotic transcription factors for myocardial protection, and the activation of SITT1 can alleviate myocardial I/RI through the FOXO1-anti-apoptotic pathway. Studies have shown that the JAK2/STAT3 and SIRT1 signaling pathways may cross-talks in many pathophysiological procedure. We first verified that: curcumin (Cur) post-treatment can be effective against myocardial I/RI through the JAK2/STAT3 signaling pathway, in addition, Cur post-treatment also increased the expression of SIRT1. Based on the appeal evidences, we hypothesize: SIRT1 and JAK2/STAT3 signaling pathways may affect each other to mediate the protective effects of Cur post-treatment, which ultimately act on the FOXO1-anti-apoptotic pathway to fight against myocardial I/RI. Rat hearts in vivo, isolated rat hearts, cardiomyocytes, gene knockout mice, Western blot, siRNA interference and other motheds will be used in this project to explore whether SIRT1 and JAK2/STAT3 signaling pathways mediates the protective effects of Cur post-treatment and its specific mechanisms. In this way, we can provide a sufficient theoretical basis for the further development and clinical application of Cur-based post-treatment methods.