Reactive and cytotoxic enals are the end products of lipid peroxidation reactions. These compounds are also present in the environment and industrial pollutants, and are generated during metabolism of several foods, drugs, and metabolites. It has been suggested that enals act as toxic second messengers that mediate the injurious effects of oxygen-derived free radicals. The heart may be particularly sensitive to enal toxicity. Nevertheless little is known in regard to the cardiac metabolism of enals. The investigator's working hypothesis is that in the heart, aldose reductase (AR)-catalyzed reduction is the major pathway for enal detoxification, and that AR-mediated enal metabolism is an antioxidative mechanism by which the heart protects itself from free radical injury. In order to test this hypothesis, using 4-hydroxynonenal and acrolein as model enals, the PI will: (a) elucidate the major biochemical pathways for enal metabolism in perfused rat hearts and isolated cardiac myocytes and assess the contribution of AR to enal metabolism; (b) examine the catalytic efficiency of cardiac AR in reducing enals and their metabolites (c) determine whether reduction diminishes enal toxicity, and examine whether selective pharmacological inhibition of AR, or augmentation of the enzyme by either kinetic stimulation or enhanced gene expression, correspondingly alters the toxicity of enals; and (d) elucidate the antioxidative role of AR in protecting isolated myocytes for hydrogen peroxide toxicity and perfused hearts from reperfusion injury. If AR-catalyzed reduction is indeed the major route for enal metabolism, then reductive products should constitute a major proportion of enal metabolites in the heart; homogeneous AR should catalyze the reduction of enals with high efficiency; and AR-catalyzed reduction should diminish the toxicity of enals as well as that initiated by free radicals. Completion of this project will furnish insights into the cardiac metabolism of enals and provide a better understanding of their physiological and pathological roles. The results obtained will also help in understanding the cardiotoxic mechanisms of several metabolites, drugs, and pollutants, and in critically evaluating the proposed role of enals act as toxic second messengers, so that more targeted clinical trials on antioxidant therapy could be designed, and more effective antioxidative interventions could be developed.
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