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Cardioprotective Efficacy ofMg-Supplementation during HAART Therapy

HAART 治疗期间补充镁的心脏保护作用

基本信息

批准号：
8147831
负责人：
Ivan Tong Mak
金额：
$ 19.37万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-24 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8147831
关键词：
3-nitrotyrosine Accounting Adverse effects Apoptosis Attenuated Blood Blood Circulation Cardiac Cardiovascular system Cell Survival Chronic Data Development Dose Dyslipidemias Echocardiography Endothelial Cells Endothelin-1 Epoprostenol Event Functional disorder Funding Generations Glucose Intolerance Glutathione Glutathione Disulfide Guidelines HIV HIV-1 Highly Active Antiretroviral Therapy ITGAM gene In Situ In Vitro Infiltration Inflammation Inflammatory Injury Injury to Kidney Interleukin-6 Iron Kidney Lipid Peroxidation Lipid Peroxides Lipids Mediating Mediator of activation protein Metabolic Metabolic Diseases Mitochondria Modeling Molecular Weight Monitor Myocardial Myocardial Infarction Neutrophil Activation Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Pathology Patients Pharmaceutical Preparations Plasma Property Protease Inhibitor Rattus Reactive Oxygen Species Regimen Reporting Risk Ritonavir Role Stress Supplementation TNF gene Techniques Tenofovir Testing Time Tissues Toxic effect United States National Institutes of Health Weight Gain Western Blotting Zidovudine base cardiovascular disorder risk caspase-3 cell injury combat cytokine cytotoxic cytotoxicity efavirenz extracellular functional disability in vivo indexing inflammatory marker isoprostaglandin F2alpha type-III neutrophil non-nucleoside reverse transcriptase inhibitors oxidation prevent protective efficacy public health relevance

项目摘要

DESCRIPTION (provided by applicant): Tenofovir (TFV), efavirenz (EFV) and ritonavir (RTV) are the first line highly active antiretroviral therapy (HAART) agents used in most treatment of HIV patients. Their uses are well documented to be associated with increased cardiovascular dysfunction and co-morbid toxicity, but the potential beneficial effect of Mg- supplementation has not been investigated. Several protease inhibitors (PI), RTV in particular, and EFV can cause elevated endothelial cell reactive oxygen species generation and cellular dysfunction. Dyslipidemia associated with PI use may also account for increased risk of myocardial infarction. Most NRTIs, TVF included, display varying degrees of mitochondrial toxicity. Our in vitro studies using cultured endothelial cells indicate that high extracellular Mg attenuated AZT-induced increases in ROS formation, decreased release of PGI2 and NO and reduced cell viability. Similar effects were observed for RTV-induced cytotoxicity. AZT treatment in a rat model provoked systemic oxidative stress, neutrophil activation and inflammatory WBC infiltration of cardiac tissue; most intriguingly, all these oxidative indices were suppressed by dietary Mg supplementation. Based on the reported findings and our own observations, we postulate that: (i) prooxidant properties of most HAARTs may directly or indirectly cause endothelial injury and related metabolic disturbance leading to cardiac dysfunction; and (ii) Mg-supplementation provides systemic and cardioprotective benefits due to its modulating role against HAART-induced oxidative toxicity. The specific aims are: 1) Establish the dose- and time- dependent systemic oxidative stress and cardiac pathogenesis and progression of dysfunction resulting from TFV, EFV, or RTV treatment in rats. 2) Determine if dietary Mg-supplementation attenuates each HAART- induced systemic pathogenesis and cardiac dysfunction through an anti-oxidative mechanism. 3) Determine the cytotoxic mechanisms of each HAART treatment in cultured endothelial cell (EC); assess the contribution of iron and inflammatory cytokines, and the protection afforded by high levels of Mg. Oxidative stress will be determined biochemically by lipid peroxidation products (8-isoprostane, lipid hydroperoxides), blood and tissue glutathione status and NO release. HAART-induced metabolic effects will be assessed (glucose intolerance, plasma lipid disturbances), and immunohistochemical and pathology techniques will be used to localize inflammatory markers and WBC infiltration. Alteration in iCAM and eNOS expression will be assessed by western blot analysis. Changes in cardiac function will be determined in situ by echocardiogram. This proposed exploratory study may reveal a potential usefulness of Mg-supplement as an effective, yet inexpensive adjunct therapy to minimize the deleterious impact of HAART-related cardiovascular oxidative and metabolic side effects. PUBLIC HEALTH RELEVANCE: The use of highly active antiretroviral therapy (HAART) agents for HIV-1 patients may cause adverse cardiovascular side effects. The proposed project will help to determine the cytotoxicity and cardiac functional impairment caused by three currently recommended HAART agents (tenofovir, efavirenz and ritonavir), and the potential beneficial effects of Mg-supplementation.

描述（由申请人提供）：替诺福韦（TFV）、依法韦仑（EFV）和利托那韦（RTV）是用于大多数HIV患者治疗的一线高效抗逆转录病毒治疗（HAART）药物。它们的使用被充分记录为与增加的心血管功能障碍和共病毒性相关，但是尚未研究Mg补充的潜在有益作用。几种蛋白酶抑制剂（PI），特别是RTV和EFV可引起内皮细胞活性氧产生升高和细胞功能障碍。与PI使用相关的血脂异常也可能导致心肌梗死风险增加。大多数NRTI，包括TVF，显示不同程度的线粒体毒性。我们在体外培养的内皮细胞的研究表明，高细胞外镁衰减AZT诱导的ROS形成增加，减少PGI 2和NO的释放，降低细胞活力。对于RTV诱导的细胞毒性观察到类似的效果。在大鼠模型中，AZT治疗引起全身氧化应激、中性粒细胞活化和心脏组织的炎性WBC浸润;最有趣的是，所有这些氧化指数都被膳食镁补充剂抑制。基于报告的发现和我们自己的观察，我们假设：（i）大多数HAART的促氧化特性可能直接或间接导致内皮损伤和相关代谢紊乱，导致心功能障碍;（ii）镁补充剂由于其对HAART诱导的氧化毒性的调节作用而提供全身和心脏保护益处。具体目标是：1）在大鼠中建立由TFV、EFV或RTV治疗引起的剂量和时间依赖性全身氧化应激和心脏发病机制以及功能障碍的进展。2)确定膳食镁补充剂是否通过抗氧化机制减弱HAART诱导的全身性发病机制和心功能障碍。3)在培养的内皮细胞（EC）中确定每种HAART治疗的细胞毒性机制;评估铁和炎性细胞因子的作用，以及高水平镁的保护作用。氧化应激将通过脂质过氧化产物（8-异前列烷、脂质氢过氧化物）、血液和组织谷胱甘肽状态以及NO释放进行生化测定。将评估HAART诱导的代谢效应（葡萄糖耐受不良、血脂紊乱），并使用免疫组织化学和病理学技术定位炎症标志物和WBC浸润。iCAM和eNOS表达的改变将通过蛋白质印迹分析来评估。将通过超声心动图原位测定心脏功能的变化。这项拟议的探索性研究可能揭示了镁补充剂作为一种有效且廉价的辅助疗法的潜在用途，可以最大限度地减少HAART相关心血管氧化和代谢副作用的有害影响。公共卫生相关性：对HIV-1患者使用高效抗逆转录病毒治疗（HAART）药物可能会导致不良的心血管副作用。拟议的项目将有助于确定目前推荐的三种HAART药物（替诺福韦，依法韦仑和利托那韦）引起的细胞毒性和心脏功能损害，以及镁补充剂的潜在有益作用。