Abstract P3047: Identification Of Role Of Intracellular Chloride Channel Clic4 In Diabetic Cardiomyopathy.

Abstract

Cardiovascular diseases are the most common cause of morbidity and mortality in Diabetic patients. Mitochondrial dysfunction is the major contributor of the myocardial structural, functional, and metabolic defects in diabetic cardiomyopathy. Activation of mitochondrial ion channel, K ATP have been shown to facilitate protection from the adverse effects of diabetic cardiomyopathy via modulating mitochondrial function. In this study we delineate the impact of mitochondrial associated membrane (MAM) chloride channel-CLIC4 in diabetic cardiomyopathy. Our results show that pharmacological inhibition of chloride intracellular channel (CLIC) with IAA-94 abrogated the cardio-deleterious effects of hyperglycemia in neonatal cardiomyocytes, thus, implicating role of targets of IAA-94 in the onset and development of diabetic cardiomyopathy. Amongst the six mammalian paralogs of CLICs, we identified CLIC4 and CLIC5 are most abundant in the heart. In addition, we observed over expression and localization changes of MAM-CLIC4 but not mitochondrial CLIC5 in neonatal cardiomyocytes upon high glucose treatment. Furthermore, cardiomyocytes isolated from CLIC4 knock out mice under hyperglycemia do no exhibit disruption of sarcomere structures, reduction in contractility, and enhanced ROS production in comparison to wild type cardiomyocytes. These observations suggest that an absence of CLIC4 revokes the structure-function changes in cardiomyocytes upon hyperglycemia. Moreover, we demonstrate that clic4 -/- mice were protected from body weight gain and impaired glucose tolerance in comparison to wild type mice in the presence of a high fat diet. Interestingly, we also observed that clic4 -/- mice are resistant to increase in blood glucose levels upon streptozocin administration. Thus, suggesting a regulatory role of CLIC4 in glucose metabolism. Overall, this study suggests a probable novel role of intracellular chloride channel CLIC4 in diabetic cardiomyopathy via regulating glucose metabolism.