ENDOTHELIN-1-- A NEW PLAYER IN DIABETIC CARDIOMYOPATHY

Auburn University At Auburn, Auburn University AL

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Abstract

DESCRIPTION Applicant's Abstract Diabetes mellitus is a metabolic disorder recently identified as a strong independent risk factor for cardiovascular disease. Both Type 1 and 2 diabetes mellitus have been linked to a marked increase in the incidence of heart failure and mortality associated with coronary heart disease. Diabetic cardiomyopathy, an independent clinical syndrome, is characterized by diastolic dysfunction, abnormalities in systolic function and histological changes that occur with or without coronary artery disease. The specific etiological mechanism(s) responsible for the cardiormyopathy observed in diabetic patients and experimental models of diabetes has not been clearly defined. However, the direct effects of abnormal carbohydrate metabolism and excessive fatty acid oxidation have been implicated as important proximate causes in diabetic cardiomyopathy. We propose that another factor contributing to altered cardiac energy metabolism and function associated with diabetic cardiomyopathy is the bioactive peptide, endothelin-1 (ET-1). In this application, we present preliminary data demonstrating that diabetic rats have elevated plasma and tissue levels of ET-1, decreased cardiac mechanical function and decreased tissue fructose-2,6-bisphosphate (F26P2) levels compared to vehicle-treated rats eight weeks after induction with streptozotocin. Furthermore, in isolated ventricular myocytes. ET-1 inhibits glucose uptake, glycolysis and F26P2 production, possibly by a protein kinase C (PKC)-dependent mechanism. We therefore hypothesize that the progressive decline in cardiac metabolism and function observed in the diabetic patient is due in part to the metabolic effects of ET-1, which augment the already altered cardiac metabolism produced by insulin deficiency/resistance and subsequent elevations in free fatty acid levels. To test this hypothesis, the following specific aims will be examined in streptozotocin (STZ)- and vehicle-treated rats: 1) Determine the cellular effects of ET-1 on cardiac glucose uptake and utilization in isolated ventricular myocytes; 2) Examine endothelin-insulin myocardial receptor signaling crosstalk in isolated ventricular myocytes and the effect of protein kinase C activation on this crosstalk; and 3) Determine the time course for the pathological effects of ET-1 on cardiac metabolism, PKC activation and function in vivo in diabetic rats using the endothelin receptor antagonist bosentan. In summary, this application will delineate the connections between altered intracellular signaling between ET-1 and insulin as they relate to glucose utilization, protein kinase C activation and myocyte function, and examine the relation between altered energy metabolism and myocardial function in diabetes mellitus. (End of Abstract)