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.
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