Abstract 842: Potential Role of MicroRNAs in the Pathogenesis of Diabetic Cardiomyopathy
Cardiac dysfunction is a common and important manifestation of diabetes mellitus and accounts for much of the increased mortality in diabetic patients. Recent studies have uncovered key roles for a family of newly discovered small non-coding regulatory RNA molecules, known as microRNAs (miRNAs), in the control of diverse aspects of cardiac function and dysfunction. However, it remains to be shown whether the expression of miRNAs is altered in the heart in response to diabetes and accounts for the pathogenesis of the disease. We have determined the expression profile of miRNAs in the heart of a rat model of type 2 diabetes using a custom Affymetrix microarray platform in order to gain a better understanding of their possible involvement in diabetic cardiomyopathy. We Identified 17 miRNAs that are differentially regulated during diabetic cardiomyopathy, suggesting that they might function as modulators of this condition. Interestingly, most of the identified miRNAs were similarly dysregulated in type 2 diabetic failing human hearts. Since type 2 diabetes is associated with insulin resistance, we further investigated the functional significance of these miRNAs by over-expression using synthetic miRNA mimics in vitro. Overexpression of a single miRNA (mir-152), which was up-regulated in diabetic cardiomyopathy, inhibited insulin-stimulated glucose uptake and induced cardiac hypertrophy in rat neonatal myocytes. Additionally, mir-152 significantly increased the Phospholamban/Serca2a ratio, suggesting abnormal calcium handling. Our results suggest that specific miRNAs play important roles in myocardial dysfunction associated with insulin resistance and may provide novel therapeutic approaches for the management of diabetes-induced cardiomyopathy.