SIRT1调控Nrf2-Drp1通路在糖尿病MIRI易损性中的作用和机制研究

Diabetes mellitus myocardial ischemia-reperfusion injury caused by the increased vulnerability of the mechanism is not clear, studies have shown that increased mitochondrial fission is one of the mechanisms of increased vulnerability, Nrf2-Drp1 signaling pathway in a variety of cells have the regulation of mitochondria The treatment of fission as a target for inhibiting mitochondrial fission is considered to be the most promising strategy for the treatment of diabetic MIRI. Our previous study found that resveratrol up-regulates the expression of SIRT1 and Nrf2 and has a protective effect on diabetic MIRI. Based on this, resveratrol mainly targets SIRT1-mediated Nrf2-Drp1 signaling pathway, and through in vitro cell experiments, Nrf2-siRNA interference, Nrf2 overexpression, Nrf2-targeted molecular agonist dimethyl fumarate, Nrf2 and SIRT1 knockout were used to investigate the role of SIRT1-mediated Nrf2- Role of Drp1 signaling pathway in the vulnerability of diabetic MIRI. And to observe the feasibility and effectiveness of resveratrol in the treatment of diabetic MIRI, and to provide new ideas and theoretical basis for clinically seeking to reduce the protective methods of diabetes MIRI.

糖尿病对心肌缺血再灌注损伤所致易损性增高的机制尚不明确，研究显示线粒体裂变增加是其易损性增高的机制之一，Nrf2-Drp1信号通路在多种细胞中均具有调控线粒体裂变的作用，以抑制线粒体裂变为靶点的治疗被认为是治疗糖尿病MIRI最有前景的策略。本课题组前期研究发现白藜芦醇通过上调SIRT1、Nrf2的表达，对糖尿病MIRI具有保护作用，在此基础上本研究拟以SIRT1介导的Nrf2-Drp1信号通路为中心，通过体外细胞实验、在体大鼠及基因敲除鼠模型，采用Nrf2-siRNA干扰、Nrf2基因过表达、Nrf2靶向分子药物富马酸二甲酯激动、Nrf2和SIRT1基因敲除等方法研究SIRT1介导的Nrf2-Drp1信号通路在糖尿病MIRI易损性机制中的作用。并观察白藜芦醇靶向治疗糖尿病MIRI的可行性及效果，进而为临床寻求减轻糖尿病MIRI的保护性方法提供新思路和理论依据。

糖尿病对心肌缺血再灌注损伤所致易损性增高的机制尚不明确，研究显示线粒体裂变增加是其易损性增高的机制之一，Nrf2-Drp1信号通路在多种细胞中均具有调控线粒体裂变的作用 ，以抑制线粒体裂变为靶点的治疗被认为是治疗糖尿病MIRI最有前景的策略。本课题组前期研究发现白藜芦醇通过上调SIRT1、Nrf2的表达，对糖尿病MIRI具有保护作用，在此基础上本研究以SIRT1介导的Nrf2-Drp1信号通路为中心，通过在体大鼠及慢病毒转染大鼠模型，采用Nrf2靶向分子药物富马酸二甲酯激动、慢病毒转染抑制Nrf2和SIRT1表达等方法研究SIRT1介导的Nrf2-Drp1信号通路在糖尿病MIRI易损性机制中的作用。并观察白藜芦醇靶向治疗糖尿病MIRI的可行性及效果，为临床寻求减轻糖尿病MIRI的保护性方法提供新思路和理论依据。本研究结果表明1、糖尿病心肌对I/R损伤敏化的因素可能与糖尿病心肌中Nrf2的异常表达有关；2、富马酸二甲酯激动Nrf2调控Drp1相关线粒体裂变减轻糖尿病大鼠心肌I/R损伤；3、白藜芦醇能激活SIRT1-Nrf2-Drp1 信号通路抑制线粒体裂变，从而减轻糖尿病大鼠心肌I/R损伤。上述结果是分子学机制向临床干预的转化，对保护围术期糖尿病心肌有重要意义。