The Ubiquitin Proteasome System in Diabetic Cardiomyopathy

The ubiquitin-proteasome system (UPS) is a major intracellular protein degradation pathway that is involved in most cellular processes. UPS dysfunction has been implicated in various cardiac diseases and is being recognized as a contributory factor to the pathogenesis of different forms of cardiomyopathies. Diabetic cardiomyopathy (DCM), a major risk factor in diabetic patients, is defined as ventricular dysfunction in absence of vascular disease. The functional status of the UPS has not been systematically investigated in the heart of diabetic animal models and the role of UPS dysfunction in the genesis of DCM has not been defined. Our preliminary data suggest that UPS proteolytic function is impaired in the early stage of DCM in a mouse model of type I diabetes. We therefore hypothesize that defective UPS proteolytic function is a major mediator for the development of DCM. To test this hypothesis, we will pursue the following specific aims using mouse models of type I diabetes: (1) systematically evaluate the change of UPS-mediated proteolytic function in diabetic hearts and analyze its temporal relationship with DCM progression in mouse models of type I diabetes; (2) determine the effects of cardiac proteasome function enhancement on DCM. A transgenic mouse model overexpressing PA28a specifically in cardiomyocytes (CR-PA28aOE) will be employed in the study; (3) investigate the vicious cycle between oxidative stress and UPS dysfunction in a hyperglycemic milieu. The reciprocal impact between reactive oxygen species (ROS) in diabetes and UPS function will be determined. The results generated from this project will yield new insights into the pathogenesis of DCM and the regulation of UPS function, thereby laying an important foundation for the development of new measures to prevent and/or more effectively treat DCM via targeting the UPS. (AHA Program: Scientist Development Grant)