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 occur in only one population of heart mitochondrial (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 injury during ischemia compared to the adult heart, and that the decrease in the energy charge and an excess of oxidative damage accounts for the increased in injury observed in the aging heart. The four interactive Projects herein will establish the mechanisms and intracellular sites of the increased damage that occurs in the aging heart during ischemia and the consequence during reperfusion. 0003 will test the hypothesis that the production of reactive oxygen species is enhanced in elderly mitochondria and chemically identify the structural damage. 0002 will test the hypothesis that complex III is the site of oxyradicals that leads, by attacking peptide subunits of cytochrome c oxidase (complex IV) in the aged heart, to oxidative damage to cardiolipin and cytochrome c, and to mitochondrial damage and dysfunction, which is accelerated owing to the Qo site defect. Approaches to limit the excess injury that occurs during ischemia and reperfusion in the aging heart will be a central thematic experiment across all Projects. 0004 will test the hypothesis that the decreased energy charge leads to phosphorylation of the enzyme carnitine palmitoyltransferase-I, the rate limiting step in fatty acid oxidation, with kinetic changes and leads to inappropriately increased fatty acid oxidation and the accompanying deleterious consequences of excess fatty acid oxidation during reperfusion. 0005 will focus on the glutaredoxin system in regulation of S-glutathionylation and apoptosis in the aged heart. The transfection of glutaredoxin isoforms into the heart provides a common experiment to examine the impact of increased protection via glutathionylation regulation for the focus within each Project.
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