Cardioprotection with mTOR Inhibition

雷帕霉素哺乳动物靶蛋白（mTOR）的过度活化和活化的STAT 3水平降低 导致急性心肌梗死后死亡率增高。基于我们令人信服的初步证据 数据，我们假设mTOR抑制剂，雷帕霉素，保护心肌缺血再灌注（I/R） 2型糖尿病（T2 D）的危害。因此，在本申请中，我们提出了新的研究来调查 雷帕霉素的心脏保护机制。我们将检查雷帕霉素治疗的效果（之前 缺血或再灌注期间）对心肌梗死面积、功能和 T2 D小鼠中的I/R。将在T2 D小鼠的心脏和心肌细胞中测定STAT 3的磷酸化。 雷帕霉素治疗STAT 3在雷帕霉素抗心肌缺血再灌注损伤中的作用 心肌细胞将在高脂饮食后的心脏特异性STAT 3缺陷小鼠中得到证实 （HFD）诱发的糖尿病。由于STAT 3正调控miR-20 a，我们将检测miR-17和miR-20 a的水平。 miR-20 a，miR-17-92簇的一部分，在雷帕霉素治疗的糖尿病心脏和心肌细胞中通过 在心脏特异性miRNA-17-92簇缺陷小鼠中通过喂食HFD诱导T2 D，我们将 证明miR-17/20 a在雷帕霉素诱导的心脏保护中的原因和作用。最后，我们将开发 并优化雷帕霉素为基础的治疗方法，以防止清醒糖尿病再灌注损伤 家兔我们将测试当雷帕霉素在心肌梗死时给药是否有效减少梗死面积。 再灌注和是否类似于db/db小鼠的信号传导机制有助于心脏保护， 转化型糖尿病兔心肌梗死模型。在完成这些研究后，我们预计 对雷帕霉素在糖尿病患者中的心脏保护作用的机制有了新的认识。 心肌我们相信，雷帕霉素将是一种有吸引力的药物，适用于临床环境， 急性心肌梗死患者。考虑到冠状动脉疾病是死亡的主要原因 在糖尿病患者中，雷帕霉素治疗可能提供一种新的心脏保护治疗选择， 公共卫生影响。

Excessive activation of the mammalian target of rapamycin (mTOR) and decreased levels of activated STAT3 in diabetic heart lead to higher mortality after acute myocardial infarction. Based on our compelling preliminary data, we hypothesize that mTOR inhibitor, rapamycin, protects against myocardial ischemia-reperfusion (I/R) injury in type 2 diabetes (T2D). Accordingly, in this application, we have proposed novel studies to investigate the mechanisms of cardioprotection with rapamcyin. We will examine the effect of rapamycin treatment (before ischemia or during reperfusion) on myocardial infarct size, function, and cardiomyocytes cell death following I/R in T2D mice. Phosphorylation of STAT3 will be determined in hearts and cardiomyocytes of T2D mice after rapamycin treatment. The essential role of STAT3 in rapamycin-induced protection against I/R injury in hearts and cardiomyocytes will be demonstrated in cardiac-specific STAT3-deficient mice following high-fat diet (HFD)-induced diabetes. Since STAT3 positively regulates miR-20a, we will examine the level of miR-17 and miR-20a, part of miR-17-92 cluster, in diabetic heart and cardiomyocytes with rapamycin treatment. By inducing T2D with the feeding of HFD in cardiac-specific miRNA-17-92 cluster-deficient mice, we will demonstrate cause and effect of miR-17/20a in rapamycin-induced cardioprotection. Finally, we will develop and optimize rapamycin-based therapeutic approach in preventing reperfusion injury in conscious diabetic rabbits. We will test whether rapamycin is effective in reducing infarct size when administered at the time of reperfusion and whether signaling mechanisms similar to db/db mice contribute to cardioprotection in this translational diabetic rabbit model of myocardial infarction. Upon completion of these studies, we expect to gain new insights into the mechanisms involved in cardioprotective effects of rapamycin in the diabetic myocardium. We believe that rapamycin would represent an attractive agent to apply to the clinical setting of acute myocardial infarction in patients. Considering that coronary artery disease is the principal cause of death in diabetic patients, rapamycin therapy may offer a novel therapeutic option for cardioprotection with enormous public health implications.