A2A/PKCα/miR-15 通路在腺苷后适应对糖尿病性大鼠心肌缺血再灌注损伤的研究

项目名称： A2A/PKCα/miR-15 通路在腺苷后适应对糖尿病性大鼠心肌缺血再灌注损伤的研究

项目编号： No.81471858

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 柯剑娟

作者单位： 武汉大学

项目金额： 69万元

中文摘要： 糖尿病患者更易发生心肌缺血再灌注(I/R)损伤，且预后更差,因此迫切需要研究糖尿病背景下心肌I/R的保护作用机制。我们既往研究表明糖尿病微环境可能抑制心肌细胞腺苷受体A2A的活性，加重心肌I/R损伤，腺苷后适应对其具有较强的保护作用，因此课题在既往研究的基础上提出腺苷可能通过其受体A2A活化PKCα，下调miR-15，最后抑制NF-κB诱导的炎性因子产生，从而对糖尿病背景下的心肌I/R损伤产生保护作用的机制学说。课题建立糖尿病大鼠在体和体外心肌细胞高糖培养模型，观察糖尿病微环境A2A活性表达状况，分别用受体抑制剂和针对大鼠miR-15基因的重组腺相关病毒载体在A2A/PKCα/miR-15通路的重要环节进行干预，探讨对腺苷后适应保护作用的影响以及可能机制。课题为腺苷后适应在糖尿病相关的心肌I/R损伤中的应用提供新的思路，也为糖尿病相关的心肌损伤治疗和预防提供新的方向和潜在治疗靶点

中文关键词： 心肌缺血再灌注损伤；糖尿病性；腺苷；后适应；微小RNA

英文摘要： Diabetic patients are more susceptible to the injury of myocardial ischemia reperfusion（I/R） and worse prognosis compared to the non diabetes. Therefore, the mechanism study of diabetic myocardial I/R is urgently needed for the effective protection strategy. Previous study showed that diabetic microenvironment may inhibit the activity of adenosine receptor (A2A) ,the adenosine postconditioning had a strong protective effect on myocardial I/R, and inhibited the inflammation.In the current study, it was proposed that the adenosine postconditioning might active PKC? via its receptor A2A, and thereby down regulating miR-15 and inhibiting the production of inflammatory cytokines, which all lead to the protection on the diabetic myocardial I/R. To prove our hypothesis, the in vitro model cell line and ex vivo myocardial I/R model were utilized to investigate the role of A2A/ PKC?. The interferences on A2A, PKC?, and miR-15 were performed to further elucidate their protective roles in the myocardial ischemia reperfusion. Our study shed a new light on the mechanism of diabetic myocardial I/R, and the protection role of adenosine postconditioning. Our findings provided a novel therapeutic target for diabetic myocardial I/R

英文关键词： myocardial ischemia-reperfusion injury;diabetic;adenosine;postconditioning;microRNA