PEROXYNITRITE INJURY IN CARDIAC HYPERTROPHY AND FAILURE

University Of Alabama At Birmingham, Birmingham AL

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Abstract

DESCRIPTION (adapted from the applicant's abstract): The applicant proposes to test the following hypothesis: The development of pressure overload hypertrophy induces nitric oxide synthase (iNOS) and results in elevated myocardial nitric oxide (NO). The elevated NO leads to increased peroxynitrite induced myocardial injury, specifically in the mitochondria, resulting in increased susceptibility to ischemic injury and leading to CHF. The applicant will use a rat model of aortic banding which causes pressure overload hypertrophy leading to CHF. Changes in NO and iNOS will be characterized over time in this model and related to functional alterations using the isolated perfused rat heart, isolated cardiac myocytes and mitochondria. The degree of peroxynitrite injury to the myocardium will be determined by immunohistochemistry and western blots to determine the degree of tyrosine nitration. Levels of NO and iNOS will be manipulated pharmacologically in order to assess their role in the development of hypertrophy and CHF. In addition, hearts will be subjected to ischemic injury and peroxynitrite infusion in order to identify specific metabolic alterations which may manifest under conditions of stress.