Role of Oxidative Stress and Inflammation in HIV Cardiovascular Risk

氧化应激和炎症在艾滋病毒心血管风险中的作用

• 批准号: 7691231
• 负责人: Cecilia M. Shikuma
• 金额: $ 90.86万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691231
• 关键词: 8-Oxo-2' -Deoxyguanosine; Adult; Age; Aging; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Atherosclerosis; Biological Markers; Blood; Body Composition; C-reactive protein; Calcium; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Chronic; Clinical; Clinical Trials; Coenzyme A; Cohort Studies; Complex; Controlled Clinical Trials; Coronary artery; Deposition; Development; Diabetes Mellitus; Dose; Double-Blind Method; Dyslipidemias; Electron Beam Tomography; Enrollment; Etiology; Event; FCGR3B gene; Fasting; Fatty acid glycerol esters; Funding; General Population; Grant; HIV; Hawaii; Highly Active Antiretroviral Therapy; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Immune; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-17; Jupiter; LDL Cholesterol Lipoproteins; Life; Lipids; Lymphocyte; Mediating; Mitochondria; Morbidity - disease rate; Morphology; Natural History; OGTT; Oxidative Phosphorylation; Oxidative Stress; Oxidoreductase; Participant; Patients; Peer Review; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Placebo Control; Play; Population; Primary Prevention; Process; Production; Property; Protease Inhibitor; Proteins; Publications; Publishing; Randomized; Reactive Oxygen Species; Recruitment Activity; Relative (related person); Research; Research Personnel; Risk; Risk Factors; Role; Secondary Prevention; Secondary to; Smoking; Source; Surrogate Markers; System; T-Lymphocyte; Testing; Time; Vascular System; Vasodilation; abstracting; atorvastatin; base; brachial artery; cardiovascular risk factor; cohort; complex IV; cytokine; enzyme activity; experience; glucose metabolism; high risk; improved; inflammatory marker; inhibitor/antagonist; mitochondrial dysfunction; monocyte; mortality; rosuvastatin; stem

DESCRIPTION (provided by applicant): HIV-infected patients now live longer because of the availability of highly active antiretroviral therapy (HAART). There is growing evidence however that HIV-infected subjects in the era of HAART are at increased risk of cardiovascular (CV) morbidity and mortality. While dyslipidemia and insulin resistance induced by protease inhibitors and other classes of HIV medications likely contribute to this increased risk, there is now substantial evidence to suggest that much of the increased CV risk may stem from the inability of these potent antiretroviral medications to completely eliminate the immune mediated chronic inflammatory effects of HIV per se on the vascular system. HMG-CoA reductase inhibitors (statins) are medications commonly prescribed to lower levels of low density lipoprotein cholesterol (LDL-C) in individuals with dyslipidemia and increased CV risk. In the general non-HIV-infected population, statins have been demonstrated to have efficacy for both primary and secondary prevention of CV events and mortality. In these studies, the reduction in CV morbidity cannot be explained completely by the known ability of statins to lower LDL-C levels and it has been hypothesized that much of the beneficial effects of these medications may be due to the anti-inflammatory properties of this class of medications. We hypothesize that the increased CV risk in the HIV population on HAART has an inflammatory component secondary to incompletely suppressed HIV-induced chronic inflammation and that statins may have efficacy in reducing such inflammation. We propose to evaluate, in 100 HIV subjects at intermediate CV risk, the effect of low dose atorvastatin on surrogate markers of CV risk over a 2 year period; specifically its effect on flow-mediated vasodilation of the brachial artery, on deposition of coronary artery calcium by electron beam tomography, and on changes in levels of hs-CRP. Within this clinical trial, we propose to assess the role of Th17 lymphocytes and their secretory compounds interleukin 17 in perpetuating the HIV-induced inflammatory process leading to increased CV risk in individuals on HAART. In addition, we propose to assess the impact of HIV-induced inflammatory processes on insulin resistance and on oxidative phosphorylation enzyme and activity levels. HIV-infected individuals may be at high risk for cardiovascular (CV) disease. We propose to establish a 150 patient cohort to look at the role of oxidative stress and inflammation as causes for this high CV risk. In addition, we propose a small clinical trial of rosuvastatin (a lipid lowering drug) in 50 patients from the cohort with evidence of inflammation (high C- reactive protein levels in blood) but low cholesterol levels, to see if the anti-inflammatory properties of this class of medication will decrease CV risk. (End of Abstract)

描述（由申请人提供）： 由于高效抗逆转录病毒疗法（HAART）的可用性，艾滋病毒感染患者现在的寿命更长。然而，越来越多的证据表明，在HAART时代，HIV感染受试者的心血管（CV）发病率和死亡率风险增加。虽然蛋白酶抑制剂和其他类别的HIV药物诱导的血脂异常和胰岛素抵抗可能导致这种风险增加，但现在有大量证据表明，CV风险增加的大部分可能源于这些强效抗逆转录病毒药物无法完全消除HIV本身对血管系统的免疫介导的慢性炎症作用。HMG-CoA还原酶抑制剂（他汀类药物）是常用于降低血脂异常和CV风险增加个体的低密度脂蛋白胆固醇（LDL-C）水平的药物。在一般非HIV感染人群中，他汀类药物已被证明对CV事件和死亡率的一级和二级预防有效。在这些研究中，CV发病率的降低不能完全由他汀类药物降低LDL-C水平的已知能力来解释，并且假设这些药物的许多有益作用可能是由于这类药物的抗炎特性。我们假设接受HAART治疗的HIV人群中CV风险增加具有继发于不完全抑制的HIV诱导的慢性炎症的炎症成分，并且他汀类药物可能具有减轻此类炎症的功效。我们建议在100例中度CV风险的HIV受试者中评价低剂量阿托伐他汀在2年内对CV风险替代标志物的影响;特别是其对血流介导的肱动脉血管舒张、电子束断层扫描冠状动脉钙沉积和hs-CRP水平变化的影响。在这项临床试验中，我们建议评估Th 17淋巴细胞及其分泌化合物白细胞介素17在维持HIV诱导的炎症过程中的作用，导致HAART个体CV风险增加。此外，我们建议评估艾滋病毒诱导的炎症过程对胰岛素抵抗和氧化磷酸化酶和活性水平的影响。HIV感染者可能有患心血管（CV）疾病的高风险。我们建议建立一个150例患者的队列，研究氧化应激和炎症作为高CV风险原因的作用。此外，我们提出了一项小型的瑞舒伐他汀（一种降脂药物）临床试验，在队列中有炎症证据（血液中C反应蛋白水平高）但胆固醇水平低的50例患者中进行，以观察这类药物的抗炎特性是否会降低CV风险。(End摘要）