心脏成纤维细胞SIRT3抑制NLRP3炎症体激活的机制及其在心肌缺血/再灌注损伤中的作用研究

项目名称： 心脏成纤维细胞SIRT3抑制NLRP3炎症体激活的机制及其在心肌缺血/再灌注损伤中的作用研究

项目编号： No.81500193

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张文波

作者单位： 江苏大学

项目金额： 18万元

中文摘要： 炎症反应是心肌缺血/再灌注（I/R）损伤的重要机制。NLRP3炎症体介导IL-1β等促炎因子的加工分泌，调节炎症反应。近来发现心脏成纤维细胞NLRP3炎症体激活在心肌I/R损伤的发生、发展中起到突出作用。但相关调控机制仍不清楚。Sirtuin3 (SIRT3) 是定位于线粒体的去乙酰化酶，起稳定线粒体功能的作用。我们初步发现，SIRT3下调线粒体ROS生成，抑制NLRP3炎症体激活。于是提出假设：成纤维细胞SIRT3通过稳定线粒体功能，抑制NLRP3炎症体激活及IL-1β等促炎因子分泌，减轻I/R诱导的心肌细胞炎症损伤。我们拟采用离体缺氧/复氧模型以及在体冠状动脉左前降支I/R模型，以SIRT3的底物 (MnSOD和亲环素D) 为中介，以线粒体ROS及mtDNA的氧化、释放为主要方向，探讨SIRT3抑制NLRP3炎症体激活的具体机制及其作用，以期为心肌I/R损伤的防治提供新的策略。

中文关键词： NLRP3炎症体；沉默信息调节因子3；；心肌缺血/再灌注损伤；线粒体功能紊乱；活性氧族

英文摘要： Inflammatory response is among the most important mechanisms involving myocardial ischemia/reperfusion injury. NLRP3 inflammasome mediates the maturation and secretion of pro-inflammatory cytokines like IL-1β and regulates inflammatory responses. Activation of NLRP3 inflammasome in cardiac fibroblasts have been recently reported to play a critical role in the initiation and development of myocardial ischemia/reperfusion injury. However, the relevant mechanisms have not been clarified yet. Surtuin3 (SIRT3) is a mitochondrial deacetylase, capable of maintaining the normal function of mitochondria through its deacetylation activity. Our preliminary study demonstrated that SIRT3 could inhibit mitochondrial ROS production and suppress NLRP3 inflammasome activation in cardiac fibroblasts. Thus we hypothesize that: SIRT3 represses activation of NLRP3 inflammasome and secretion of pro-inflammatory cytokines by regulation of mitochondrial function, oxidative stress, and hence abates cardiomyocytes inflammatory injury during myocardial ischemia/reperfusion. Based on an anoxia/reoxygenation model in vitro and left anterior descending coronary artery ischemia/reperfusion model in vivo, we try to clarify the detail mechanisms how SIRT3 inhibits the activation of NLRP3 inflammasome by targeting the substrates of SIRT3 (MnSOD and CypD), and mitochondrial ROS as well as release of oxidized mtDNA. The study will be hopeful to provide a new strategy for prevention and treatment of the related diseases.

英文关键词： NLRP3 inflammasome;sirtuin3 (SIRT3) ;myocardial ischemia/reperfusion injury ;mitochondrial dysfunction;reactive oxygen species