Role of Oxidative Stress in Post-MI Cardiac Failure Associated with Diabetes

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DESCRIPTION (provided by applicant): Patients with Diabetes Mellitus (DM) have a higher incidence of death after myocardial infarction (MI) than do non-diabetic patients. The excess mortality of diabetic MI patients has been demonstrated to result primarily from an increased incidence of heart failure (HF). Given the explosive gain in the prevalence of diabetes among both children and adults in the United States, it is likely that the incidence of cardiovascular disease and mortality will continue to increase in this high-risk population. The long-term goals of our studies is to better understand the pathophysiological mechanisms that lead to depressed cardiac function and a higher frequency of HF among diabetic patients with MI. Although there is a state of increased oxidative stress conferred by diabetes, the mechanisms by which free radical-mediated oxidative stress induces cardiac damage and ultimately cardiac dysfunction remains unclear. The objective of this proposal is to elucidate the downstream underlying mechanisms that mediate the deleterious effects of diabetes-induced free radical- mediated lipid peroxidation on heart function and to use this knowledge to develop novel therapies. Our preliminary data has shown that the levels of 8-iso-PGF21, a product of the isoprostane pathway of lipid peroxidation and sensitive marker of oxidative stress, are significantly greater in diabetic versus non-diabetic post-MI hearts. We propose that 8-iso-PGF21 and isoketals (IsoKs), both reactive lipid species formed from oxidation of lipids, play a fundamental role in the greater propensity of diabetic myocardium for oxidative stress injury and resultant HF after MI. The specific aims of the proposed project are: 1) to determine the functional response of diabetic post-MI hearts to one of the vasoactive F2-IsoPs, 8-iso-PGF21 (15-F2t-IsoP), and the mechanism underlying its actions; 2) to measure myocardial formation and localization of IsoK-protein adducts and identify cardiac-specific targets of protein oxidation in diabetic post-MI hearts using proteomic and oxyblot analyses, and 3) to rescue diabetic post-MI hearts from oxidant imposed HF by therapy with antioxidants and IsoK scavengers. All studies will be performed using the streptozotocin (STZ)-diabetic rat in a well-established rat model of HF due to MI by coronary artery ligation. The injection of STZ in rats leads to the development of hyperglycemia, excessive urination, and loss of weight, all of which mimics human type I diabetes. A broad multidisciplinary approach will be used that will encompass diverse techniques (integrative physiology, protein chemistry, biochemistry, immunohistochemistry, proteomics, pathology, and histology) and will integrate proteomic and biochemical information at the molecular level with physiological information at the whole animal level. This molecular physiologic strategy will yield novel information that is physiologically relevant.