Diabetic patients, both Type 1 and 2 display both increased incidence of cardiovascular disease, and complications of myocardial infarction and heart failure. Altered cardiac function, metabolism of glucose and fatty acids, and sodium homeostasis have been demonstrated in both types of diabetes. Altered glucose metabolism, in particular, flux of glucose via the polyol pathway may be responsible, in part, for the enhanced vulnerability of diabetic myocardium to ischemic injury. In polyol pathway, glucose is reduced to sorbitol by aldose reductase (AR) and subsequently oxidized to fructose by sorbitol dehydrogenase (SDH). We have demonstrated that flux via the polyol pathway is partly responsible for impaired myocardial glycolysis and energy production. When diabetic hearts are subjected to ischemia, the ability to generate sufficient high-energy phosphates for maintaining myocyte viability and for sodium homeostasis is severely compromised. Our work, as well as that of others, has shown that enhancement of glycolytic metabolism during ischemia is a feasible approach to maintain myocyte viability, energy metabolism and sodium homeostasis. In this context, our preliminary data demonstrate increased AR and SDH activities in both type 1 and Type 2 diabetic rat hearts and that pharmacological inhibition of AR normalized glycolysis and Na+,K+-ATPase activity via protein kinase C-B Induction of ischemia further increases AR and SDH activity in diabetic hearts and is associated with increased myocardial ischemic injury and poor functional recovery on reperfusion. Inhibition of the polyol pathway reduced ischemic injury, attenuated changes in intracellular sodium homeostasis, and improved functional and metabolic recovery after ischemia in diabetic hearts. ? ? These data lead to the hypothesis that in Type 1 and 2 diabetes, increased activity of polyol pathway enzymes AR and SDH increases myocardial vulnerability to ischemic injury, and that this can be attenuated by polyol pathway inhibitors. Mechanisms by which diabetes increases myocardial AR activity, how augmented AR activity in diabetes and ischemia acts to increase myocardial damage, and impairs sodium homeostasis and energy metabolism will be investigated. Type 1 and Type 2 diabetic and non-diabetic littermate rats, as well as transgenic mice, will be used to test our hypothesis and elucidate mechanisms using NMR spectroscopy, biochemical, and molecular techniques. The proposed studies will provide a rationale for the use of polyol pathway inhibitors as an adjunctive therapeutic intervention for treating diabetic patients with myocardial infarction.
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