Abstract
We investigated the role of polyol pathway enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH) in mediating injury due to ischemia-reperfusion (IR) in Type 2 diabetic BBZ rat hearts. Specifically, we investigated, (a) changes in glucose flux via cardiac AR and SDH as a function of diabetes duration, (b) ischemic injury and function after IR, (c) the effect of inhibition of AR or SDH on ischemic injury and function. Hearts isolated from BBZ rats, after 12 weeks or 48 weeks diabetes duration, and their non-diabetic littermates, were subjected to IR protocol. Myocardial function, substrate flux via AR and SDH, and tissue lactate:pyruvate (L/P) ratio (a measure of cytosolic NADH/NAD+), and lactate dehydrogenase (LDH) release (a marker of IR injury) were measured. Zopolrestat, and CP-470,711 were used to inhibit AR and SDH, respectively. Myocardial sorbitol and fructose content, and associated changes in L/P ratios were significantly higher in BBZ rats compared to non-diabetics, and increased with disease duration. Induction of IR resulted in increased ischemic injury, reduced ATP levels, increases in L/P ratio, and poor cardiac function in BBZ rat hearts, while inhibition of AR or SDH attenuated these changes and protected hearts from IR injury. These data indicate that AR and SDH are key modulators of myocardial IR injury in BBZ rat hearts and that inhibition of polyol pathway could in principle be used as a therapeutic adjunct for protection of ischemic myocardium in Type 2 diabetic patients.
Highlights
Cardiovascular disease represents the major cause of morbidity and mortality in patients with diabetes
We investigated the role of polyol pathway in mediating injury due to ischemia-reperfusion in Type 2 diabetic BBZ rat hearts
We demonstrate that cytosolic lactate/pyruvate ratio, a measure of cytosolic NADH/NAD, is associated with increases in polyol pathway activity in type 2 diabetic BBZ rat hearts
Summary
Cardiovascular disease represents the major cause of morbidity and mortality in patients with diabetes. Diabetic patients with coronary artery disease have high morbidity and mortality due to cardiovascular complications, with the incidence of heart failure after myocardial infarction significantly greater in patients with diabetes than in nondiabetic patients [1,2,3,4]. A spontaneous Type 2 diabetic rat BBZDR/Wor (BBZ), from Biomedical Research Models (Worcester, MA) has been shown to closely mimic human disease. This model is characterized by spontaneous onset of diabetes at approximately 70 days of age, preceded by obesity. It shows insulin resistance with hyperglycemia and hyperinsulinemia as well as hyperlipidemia, hypercholestrolemia and mild hypertension [13,14,15]
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