Protection by Thiazolidinediones in Myocardial Ischemia

说明(申请人提供)：噻唑烷二酮类化合物 过氧化物酶体增殖物相关受体(PPAR)-γ是PPAR的关键协调者 细胞能量底物代谢。噻唑烷二酮类药物临床上用于 治疗II型糖尿病。这个实验室已经证明了慢性治疗 使用噻唑烷二酮类药物的正常、非糖尿病猪可促进恢复 在体脑缺血再灌流后左心功能。 该项目将检验以下假设：噻唑烷二酮类化合物可提高回收率 改善缺血后心功能，减少心肌梗死面积 心肌基因表达和能量底物的特异性变化 与PPAR-伽马激活有关的代谢。尤其是，它是 慢性噻唑烷二酮治疗非糖尿病猪的假说 通过以下方式改善缺血和再灌流后心功能的恢复： 1.增加心肌葡萄糖转运蛋白GLUT1和GLUT4的表达， 从而促进葡萄糖摄取，提高心肌胰岛素水平 灵敏性 2.增加再灌注心肌中碳水化合物底物的氧化 3.增加心肌解偶联蛋白-2的表达，这可能有助于 减轻再灌流期间的氧化剂损伤 4.降低心肌促炎症和负性肌力的表达 细胞因子，如肿瘤坏死因子-α 如果拟议的研究证实了PPAR-伽马激活的这些有益作用 对于噻唑烷二酮类药物，这一结果可能会提出一种重要的新疗法 为患有缺血性心脏病的患者制定的战略，即使是那些没有糖尿病的患者也是如此。

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.