Our long-term goal is to develop a strategy to decrease the excess myocardial injury in elderly patients following an acute myocardial infarction. We have developed an approach to study this problem in the elderly Fischer 344 rat model. The isolated, buffer perfused elderly heart sustains greater injury after ischemia and reperfusion compared to the adult heart. At baseline, aging-defects in the mitochondrial electron transport chain occurs in only one population of heat mitochondria (interfibrillar) in elderly Fischer 344 rats. Following ischemia there is further damage to the interfibrillar mitochondria. We propose that aging- related defects in mitochondrial oxidative metabolism present at baseline in the elderly heart predispose to a subsequent increase in oxidative injury during ischemia and reperfusion compared to the adult heart, and that an excess of oxidative damage accounts for the increase in injury observed in the aging heart. The five interactive projects herein will use interventions that are designed to reduce the excess injury in the aging heat as tools to establish and intracellular sites of the increased damage that occurs in the aging heart during ischemia and reperfusion. We will test the hypothesis that the increase in Tumor Necrosis Factor alpha observed in aging tissue to the aging-related defect in complex II in interfibrillar mitochondria in the aging heart. We will determine if therapeutic intervention with a cell-permeable antioxidant N-2- mercaptopropionylglycine will protect the aging heart against the excess injury that occurs during ischemia and reperfusion, and will challenge the hypothesis that the tandem ischemic and aging-related defects in complex III in interfibrillar mitochondria increases damage in the aging heart via oxidative mechanisms. We will determine this structural basis of the ischemic defect in the Rieske iron-sulfur protein in complex III in interfibrillar mitochondria, and if the iron-sulfur protein sustains additional oxidative damage during reperfusion. We will test the hypothesis that oxidative damage to the enzyme carnitine palmitoyltransferase-I, the rate limiting step in fatty acid oxidation, occurs in interfibrillar mitochondria and leads to inappropriately increased fatty acid-oxidation and the accompanying deleterious consequences of excess fatty acid oxidation during reperfusion. We will challenge the hypothesis that a decrease in antioxidant defense mechanisms, including thioltransferase, in the aging heart results in increased oxidative injury.
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