MOLECULAR BASIS OF DIABETIC CARDIOMYOPATHY

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DESCRIPTION Applicant's Abstract Diabetic cardiomyopathy is a problem of great clinical and epidemiologic importance. Pilot studies leading to this proposal have, for the first time, identified specific alterations of myocardial dynamic stiffness of contractile and diastolic noncontratile components of left ventricular tissue from diabetic patients. Our primary hypothesis is that diabetic cardiomyopathy is multifactorial, with major contributions to the observed stiffness changes arising from connective tissue proliferation, protein crosslinking caused by deposition of myofibrillar advanced glycated end products (AGEs), and damage associated with reactive oxygen species (ROS). Myocardial proteins that are excessively glycated or damaged by ROS will be identified in diabetic myocardium, and the extent of glycation or ROS damage will be correlated with changes in various components of the myocardial dynamic (visco-elastic) stiffness in the same tissue. From previous studies, the proteins most likely to be affected are interstitial collagen, contractile proteins including actin and myosin, and myofibrillar-bound creatine kinase. Discovery of strong correlations between altered structure and function will be followed up by determining whether similar changes in function can be induced in vitro in non-diabetic myocardium. Chemical treatments will be used to induce glycation or ROS damage to the same myocardial proteins involved in altered structure-function correlations discovered in the diabetics. The efficacy of various pharmacological agents (currently of therapeutic interest as potential AGE cross-link breakers) in reversing the specific structural and functional defects found in diabetic myocardium and mock-diabetic myocardium prepared by glycation/ROS damage to non-diabetic human myocardium. This research will contribute to understanding and treating human myocardial pathologies that arise from diabetes mellitus, with particular attention to diastolic dysfunctions. (End of Abstract)