Polyol Pathway and Ischemic Injury in Diabetic Hearts

Type 1 Diabetic patients display both increased incidence of cardiovascular disease, and complications of myocardial infarction (heart attack) and heart failure. Altered glucose metabolism in diabetes, specifically, flux of glucose via AR pathway, may be responsible, at least in part, for the enhanced vulnerability of diabetic myocardium to ischemic injury. By the AR pathway, glucose is reduced to sorbitol by aldose reductase(AR) and subsequently oxidized to fructose by sorbitol dehydrogenase (SDH). In this context, our earlier studies, demonstrated activation of myocardial AR during ischemia. Furthermore, it was shown that inhibiting flux via AR reduced ischemic injury, improved functional recovery and energy levels, and was associated with attenuation of changes in sodium and calcium in Type 1 diabetic rat hearts. While the earlier studies showed that inhibition of AR protected ischemic myocardium, the mechanism by which increased AR activity mediates ischemic injury remains to be addressed. The aim of the proposed research is to delineate the mechanisms by which increased AR activity mediates ischemic injury in diabetics. Recent studies in the literature suggest that (a) mitochondria are severely damaged in diabetic hearts, and (b) signaling mechanisms converging on to glycogen synthase kinase (GSK-3¿) are altered after ischemia/reperfusion. We will determine if AR activation impairs mitochondrial function, increases oxidant stress and facilitates opening of mitochondrial permeability pore, and signals activation of GSK-3¿ in Type 1 diabetic hearts after I/R. Mechanisms by which AR pathway impacts signal transduction and mitochondrial function, and how these changes in diabetes and ischemia act to increase myocardial damage will be investigated. Strategies to determine mechanisms include the use of: (a) pharmacological inhibitors of AR and SDH in Type 1 diabetic rats and mice. We will employ isolated perfused heart model to determine mechanisms.