Protective Efficacy of Mg-Supplementation Against NRTI-induced Cardiac Toxicity

补充镁对 NRTI 诱导的心脏毒性的保护作用

• 批准号: 7229233
• 负责人: Ivan Tong Mak
• 金额: $ 22.95万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229233
• 关键词: free radicals; inflammation; injury; iron; oxidative stress; salts; stress; tissues

DESCRIPTION (provided by applicant): Zidovudine (AZT) cardiotoxicity in HIV patients has been well documented, but the potential beneficial effect of magnesium (Mg)-supplementation has never be explored. AZT toxicity is linked to increased oxidative stress which may be mediated by abnormal iron status. Since other clinically used nucleoside reverse transcriptase inhibitor (NRTI) drugs are structurally similar to AZT, their potential interaction with endogenous iron may represent a common mechanism of oxidative toxicity. Our in vitro studies suggest that AZT synergizes with iron in causing endothelial cytotoxicity and that supra levels of extracellular magnesium are cytoprotective. This proposal will explore whether dietary supplementation of either Mg oxide (inorganic) or Mg gluconate (an organic salt) will attenuate chronic NRTI-induced systemic inflammation and cardiac injury n vivo, and if the protective mechanism(s) associated with the Mg supplements can be revealed using NRTI- treated in vitro models. The specific aims are: (1) Determine the differential protective effects of upplemental inorganic and organic Mg-salts against AZT (and other NRTIs)-mediated membrane and endothelial cell oxidative injury; (2) Assess if dietary supplementation of Mg-salts (Mg oxide and Mg- gluconate: 3 and 6- fold higher than normal) in the rat attenuates chronic AZT-induced cardiovascular inflammation, oxidative stress, and neutrophil activation; and (3) Determine if Mg-supplementation attenuates AZT-enhanced myocardial susceptibility to imposed ischemia/reperfusion (I/R) stress ex vivo. We will employ immunohistochemical and pathology techniques to localize inflammatory cyokines and white blood cell infiltrates. Oxidative stress in vivo will be determined biochemically by changes in tissue/blood glutathione status, iron status, and lipid peroxidation products (F2-isoprostanes, conjugated dienes). Changes in tolerance to perfused heart l/R-stress will be determined by free radical production (ESR spin trapping), and alterations in oxidative tissue injury markers and functional recovery. This proposed exploratory effort may reveal a potential usefulness of Mg-supplements as an effective, yet relatively inexpensive adjunct therapy to lessen NRTI-related cardiovascular toxicity.

描述(申请人提供)：齐多夫定(AZT)对HIV患者的心脏毒性已有很好的文献记载，但补充镁(Mg)的潜在益处从未被探索过。AZT的毒性与氧化应激增加有关，氧化应激可能是由铁状态异常介导的。由于其他临床使用的核苷逆转录酶抑制剂(NRTI)药物在结构上与AZT相似，它们与内源性铁的潜在相互作用可能代表了一种常见的氧化毒性机制。我们的体外研究表明，AZT与铁在引起内皮细胞毒性方面具有协同作用，而细胞外过量的镁具有细胞保护作用。这项建议将探索在体内补充氧化镁(无机)或葡萄糖酸镁(一种有机盐)是否可以减轻硝酸甘油诱导的慢性全身炎症和心脏损伤，以及补充镁的保护机制(S)是否可以用硝酸甘油酯治疗的体外模型来揭示。这些研究的具体目的是：(1)确定补充无机和有机镁盐对AZT(和其他NRTI)介导的膜和内皮细胞氧化损伤的不同保护作用；(2)评估饮食中添加镁盐(氧化镁和葡萄糖镁：分别是正常水平的3倍和6倍)是否可以减轻由AZT诱导的慢性心血管炎症、氧化应激和中性粒细胞激活；(3)确定补镁是否可以减轻AZT增强的心肌对外加缺血/再灌注(I/R)应激的敏感性。我们将使用免疫组织化学和病理学技术来定位炎性细胞因子和白细胞浸润物。体内的氧化应激将通过组织/血液谷胱甘肽状态、铁状态和脂质过氧化产物(F2-异前列腺素、共轭双烯)的变化来确定。心脏对L/R灌流应激耐受性的变化将取决于自由基的产生(电子自旋共振捕获)，以及氧化组织损伤标志物和功能恢复的变化。这项拟议的探索性努力可能会揭示镁补充剂作为一种有效但相对便宜的辅助疗法在减轻NRTI相关心血管毒性方面的潜在用处。