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

心肌病：AZT 的促氧化作用

• 批准号: 6537840
• 负责人: William Bernard Weglicki
• 金额: $ 34.2万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537840
• 关键词: HIV infections; NMDA receptors; capillary electrophoresis; cytokine; disease /disorder model; laboratory mouse; laboratory rat; magnesium deficiency; model design /development; murine AIDSs; myocarditis; natural killer cells; nutrient drug interaction; oxidative stress; reperfusion; tocopherols; zidovudine

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.

描述（摘要）：艾滋病毒相关心肌病的发病机制仍然是 不清楚，很可能有多因素的原因。临床数据 发现病毒和心肌炎都存在，但通常是分开的， 区域，表明HIV可能发挥间接细胞毒性作用。艾滋病病毒 感染和药物治疗（AZT，喷他脒）可能有助于氧化 应激和镁消耗。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，我们记录了镁缺乏症 引发氧化性心肌炎我们假设药物 AZT治疗可能与喷他脒和镁缺乏协同作用， 神经源性炎症事件导致氧化应激， 心肌病为了验证这一假设，我们建议使用大鼠模型， 培养的心血管细胞，以确定AZT的促氧化作用（Aim 1)或与镁缺乏共存，以诱发心肌病， 缺血/再灌注（I/R）应激的功能障碍（目的2）。我们将 通过NMDA和NK-1受体阻断剂以及 维生素E（Aim 3）。与A博士合作。国立卫生研究院的Basile， 采用小鼠艾滋病（MAIDS）模型来评估 病毒和镁缺乏的氧化发病机制和可能的 介入治疗（目的4）。我们将使用敏感的免疫化学 技术来量化神经肽和细胞因子，并与 美国红十字会荷兰实验室的豪登希尔德博士， 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巯基状态来确定， 脂质过氧化和一氧化氮产物的积累，并通过游离 自由基的产生和离体灌注I/R心脏的损伤。我们预计 这些活体动物、组织和细胞研究的信息 可能导致潜在的诊断标准和治疗的患者的风险， 因为艾滋病而出现心肌病