Aging human subjects display increased incidence of cardiovascular disease and complications ofmyocardial infarction and heart failure. We have demonstrated that flux via the polyol pathway is partlyresponsible for impaired myocardial glycolysis and energy production. When hearts from aged rats aresubjected to ischemia, the ability to generate sufficient high energy phosphates for maintaining myocyteviability and sodium homeostasis is severely compromised. Our work, as well as that of others, has shownthat enhancement of glycolytic metabolism during ischemia is a feasible approach to maintain myocyteviability, energy metabolism and sodium homeostasis. In this revised application, we show that in humanaging, that is, without superimposed cardiovascular disease or diabetes, and in aged Fischer 344 rats,expression and activity of aldose reductase (AR) is increased in the heart. Induction of ischemia furtherincreases AR activity in aged hearts, and is associated with increased myocardial ischemic injury and poorfunctional recovery on reperfusion. Inhibition of the polyol pathway (AR) or the next enzyme in the pathway,sorbitol dehydrogenase (SDH) reduced ischemic injury, attenuated changes in intracellular sodiumhomeostasis, and improved functional and metabolic recovery after ischemia in aged hearts. Thus, wehypothesize that in aging, increased activity of the polyol pathway enzyme AR increases myocardialvulnerability to ischemic injury, and that this can be attenuated by polyol pathway inhibitors. The proposedstudies will probe the mechanisms by which aging increases myocardial polyol pathway activity, and howthis augmented activity in aging and ischemia acts to increase myocardial damage Distinct strategiesincluding pharmacological inhibitors of AR and SDH, Fischer 344 rats, and human AR expressing transgenicmice will be employed to test these concepts. Further, to enhance understanding of SDH in aging in theheart, SDH null mice will be bred into the transgenic mouse background in which human-relevant levels ofAR are expressing. We will utilize NMR spectroscopy, biochemical, and molecular techniques in ourexperiments. Project 1 is closely linked to Projects 2&3, as each studies aging-linked enhanced vulnerabilityto I/R stress in vascular cells and cardiomyocytes. Project 1 shares mouse/rat models with Projects 2 and 3.Project 1 will utilize all three Cores of the Program Project during all five years of the grant.
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