Protection by Thiazolidinediones in Myocardial Ischemia

说明（由申请人提供）：噻唑烷二酮是 过氧化物酶体增殖物相关受体（PPAR-gamma），一个关键的协调者， 细胞能量底物代谢噻唑烷二酮类在临床上用于 治疗II型糖尿病。这个实验室已经证明长期治疗 用噻唑烷二酮药物治疗正常的非糖尿病猪， 在体缺血和再灌注后的左心室功能。 本项目将检验噻唑烷二酮类药物改善恢复的假设 缺血后心功能的改善，并通过 心肌基因表达和能量底物的特异性改变 与PPAR-gamma激活偶联的代谢。特别是 假设非糖尿病猪的慢性噻唑烷二酮治疗 通过以下方式改善缺血和再灌注后的心脏功能恢复： 1.增加心肌葡萄糖转运蛋白GLUT 1和GLUT 4的表达， 从而促进葡萄糖摄取并增强心肌胰岛素 灵敏度 2.增加再灌注心肌中碳水化合物底物的氧化 3.增加解偶联蛋白-2的心肌表达，这可能有助于 减轻再灌注过程中的氧化损伤 4.减少心肌促炎性和负性肌力的表达 细胞因子，如肿瘤坏死因子-α 如果拟议的研究证实了PPAR-gamma激活的这些有益作用， 与噻唑烷二酮类药物相比， 缺血性心脏病患者的治疗策略，即使是那些没有糖尿病的患者。

DESCRIPTION (provided by applicant): Thiazolidinediones are ligands of the peroxisome proliferator associated receptor (PPAR)-gamma, a key orchestrator of cellular energy substrate metabolism. Thiazolidinediones are used clinically to treat Type II diabetes. This laboratory has demonstrated that chronic treatment of normal, non-diabetic pigs with a thiazolidinedione drug improves recovery of left ventricular function after ischemia and reperfusion in vivo. This project will test the hypothesis that thiazolidinediones improve recovery of cardiac function after ischemia and reduce myocardial infarct size through specific alterations of myocardial gene expression and energy substrate metabolism that are coupled to PPAR-gamma activation. In particular, it is hypothesized that chronic thiazolidinedione treatment of non-diabetic pigs improves recovery of cardiac function after ischemia and reperfusion by: 1. Increasing myocardial expression of glucose transporters GLUT1 and GLUT4, thereby facilitating glucose uptake and enhancing myocardial insulin sensitivity 2. Increasing the oxidation of carbohydrate substrates in reperfused myocardium 3. Increasing myocardial expression of uncoupling protein-2, which may serve to mitigate oxidant injury during reperfusion 4. Decreasing myocardial expression of pro-inflammatory and negative inotropic cytokines, such as tumor necrosis factor-alpha If the proposed studies confirm these salutary effects of PPAR-gamma activation with thiazolidinediones, the results may suggest an important new treatment strategy for patients with ischemic heart disease, even those without diabetes.