CARDIOMYOPATHY:PRO-OXIDANT ROLE OF AZT & MG-DEFICIENCY

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DESCRIPTION (Abstract): The pathogenesis of HIV-related cardiomyopathy remains unclear and most likely may have multifactorial causes. Clinical data have revealed that both the virus and myocarditis are present, but often in separate areas, suggesting that HIV may play an indirect cytotoxic role. Both the HIV infection and drug therapy (AZT, pentamidine) may contribute to oxidative stress and Mg wasting. Clinical studies have indicated that HIV/AIDS patients may be deficient in Mg. In our studies, we have documented that Mg-deficiency triggers oxidative cardiomyopathic inflammation. We hypothesize that the drug therapy with AZT may synergize with pentamidine and Mg-deficiency to initiate neurogenic inflammatory events leading to oxidative stress and eventual cardiomyopathy. To test this hypothesis, we propose to use a rat model and cultured cardiovascular cells to determine the prooxidant effects of AZT (Aim 1) or with co-existing Mg-deficiency to induce cardiomyopathy, and cardiac dysfunction with imposed ischemia/reperfusion (I/R) stress (Aim 2). We will assess the therapeutic interventions by NMDA and NK-1 receptor blockade and by vitamin E (Aim 3). In collaboration with Dr. A. Basile of NIH, we will also employ the murine AIDS (MAIDS) model to assess the synergistic contributions of the virus and Mg-deficiency to the oxidative pathogenesis and possible interventional therapy (Aim 4). We will employ sensitive immunochemical techniques to quantify neuropeptides and cytokines, and in collaboration with Dr. Haudenschild of the American Red Cross Holland Laboratory, to characterize histopathological progression in cardiac and skeletal muscles. Oxidative stress will be determined by measuring tissue glutathione and thiol status, accumulation of lipid peroxidation and nitric oxide products, and by free radical production and injury to isolated perfused I/R hearts. We anticipate that the information from these in vivo animal, tissue, and cellular studies may lead to potential diagnostic criteria and therapy for patients at risk of developing cardiomyopathy due to HIV disease.