Hyperglycemic and hyperlipidemic conditions lead to dysregulation of insulin mediated cell signaling and metabolic abnormalities. A pro-oxidative milieu exists in type II diabetes which results in increased cardiac mitochondrial production of reactive oxygen species and nitric oxide synthase activity. This proposal focuses on the central hypothesis that one class of ?NO-dependent oxidation and nitration products, nitrated fatty acids (NO2-FA), are generated in heart mitochondria under hyperglycemic conditions and can mediate reactions that beneficially modify mitochondrial function. NO2-FA derivatives are present endogenously and mediate anti- inflammatory effects through predominately cGMP-independent mechanisms that include electrophilic post- translational protein modification and potent peroxisome proliferator-activated receptor (PPARg) ligand activity. As a result of robust thiol reactivity, NO2-FA also activate phase II enzyme expression in vitro (e.g., heme oxygenase 1, HO-1), through nuclear factor E2-related factor 2 (Nrf2) activation of antioxidant response element (ARE) dependent gene expression. Current knowledge supports that in type II diabetes, a pro- oxidative milieu exists that promotes fatty acid nitration.
Three specific aims are designed to test the hypothesis that mitochondrial fatty acid nitration occurs and that these species may beneficially modify mitochondrial and cardiovascular function in type II diabetes: 1) quantify the mitochondrial production of NO2- FA in hyperglycemic wildtype and diabetic Lepob mice, 2) determine whether administered OA-NO2 modulates mitochondrial function in a diabetic-leptin deficient (ob/ob) murine model, and 3) assess changes in cardiac contractility, function, and oxygen consumption following OA-NO2 administration in Lepob diabetic mice. Completion of the proposed aims will lend insight into how NO2-FA can impact mitochondrial respiratory function, myocardial efficiency, and cardiac contractility in a murine model of diabetes. This work is of substantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2 formed as an adaptive cell signaling mediator in hyperglycemic-induced myocardial injury.
This work is of substantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2 formed as an adaptive cell signaling mediator in hyperglycemic-induced myocardial injury.
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