Diabetes is associated with cardiac dysfunction, due in part to changes in substrate utilization and mitochondrial dysfunction. We have recently found that mitochondrial ROS overproduction impairs myocardial energetics in the hearts of diabetic rodents. The goal of this exploratory and developmental R21 proposal is to test the efficacy of direct myocardial administration of various anti-oxidants preparations to reduce myocardial ROS overproduction and restore myocardial bioenergetics. We will utilize a novel polymer based drug delivery system that can be directly instilled into the pericardial sac of mice. The polymer is aqueous at room temperature but forms a stable gel at body temperature and allows for sustained delivery of compounds directly to the heart over 30 days, without altering in vivo hemodynamics. In addition to sustained delivery, this approach has the advantage of enabling the administration of relatively insoluble, unstable or expensive substances at high local concentration without the potential of deleterious systemic effects. The proposed studies will test the following hypothesis.(1) That direct myocardial administration of a potent cell-permeable SOD mimetic (MnTBAP) to the myocardium will reduce ROS production and enhance mitochondrial energetics in a mouse model of severe type 2 diabetes the db/db mouse. (2) That mitochondrial targeting of naturally occurring anti-oxidants (Vitamin E, Coenzyme Q and the flavonoid Quercetin) via TPP conjugation will enhance their efficacy in reducing myocardial mitochondrial ROS generation in diabetic hearts. (3) That a combination of naturally occurring antioxidants (ascorbic acid or alpha-tocopherol) with dihydro-alpha lipoic acid will have increased efficacy in reducing mitochondrial ROS overproduction in diabetic hearts than single agents alone. Mitochondrial superoxide and hydrogen peroxide generation, as well as oxygen consumption and ATP production will be determined ten-days following the administration of anti-oxidant compounds. This approach provides a novel and cost effective means to directly and rapidly screen a large number of potential agents for efficacy in reducing mitochondrial superoxide overproduction in cardiac mitochondria in vivo. Once efficacy is determined, promising reagents can then be subjected to pharmacokinetic and toxicological analysis following systemic administration.
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