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

描述(摘要)：HIV相关心肌病的发病机制仍然存在 目前尚不清楚，而且很可能是由多因素造成的。临床数据显示 据透露，病毒和心肌炎都存在，但通常是分开的 这表明艾滋病毒可能起到间接的细胞毒性作用。两人都是艾滋病人 感染和药物治疗(AZT、扑热息痛)可能导致氧化 压力和镁的消耗。临床研究表明，艾滋病毒/艾滋病患者 可能缺乏镁。在我们的研究中，我们证明了镁缺乏 引发氧化性心肌病炎症。我们假设这种药物 AZT治疗可能与戊二氮和镁缺乏症协同启动 神经源性炎症事件导致氧化应激并最终 心肌病。为了验证这一假设，我们建议使用一个大鼠模型和 测定AZT(AIM)对体外培养的心血管细胞的促氧化作用 1)或合并缺镁引起心肌病，心脏 施加缺血/再灌流(I/R)应激时的功能障碍(目标2)。我们会 通过阻断NMDA和NK-1受体以及通过 维生素E(目标3)。在与NIH的A.Basile博士的合作下，我们还将 使用小鼠艾滋病(女佣)模型来评估 病毒和镁缺乏对氧化的致病作用及可能 介入治疗(目标4)。我们将使用敏感的免疫化学物质 量化神经肽和细胞因子的技术，并与 美国红十字会荷兰实验室的霍登斯柴尔德博士 心肌和骨骼肌的组织病理学进展。氧化应激 将通过测量组织谷胱甘肽和硫醇状态来确定， 脂质过氧化和一氧化氮产物的积累，以及自由 自由基的产生和对离体I/R心脏的损伤。我们期待着 来自活体动物、组织和细胞研究的信息 可能导致潜在的诊断标准和治疗有风险的患者 由艾滋病毒引起的心肌病。

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.