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; 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）： 由于高度活跃的抗逆转录病毒疗法（HAART）的可用性，HIV感染的患者现在寿命更长。然而，有越来越多的证据表明，在HAART时代，受HIV感染的受试者的心血管（CV）发病率和死亡率增加。尽管蛋白酶抑制剂和其他类型的HIV药物引起的血脂异常和胰岛素抵抗可能会导致这种风险增加，但现在有大量证据表明，大部分CV风险可能导致这些有效的抗逆转录病毒药物无法完全消除HIM介导的HIV PER per eN eN An the Perasular System的慢性炎性影响。 HMG-COA还原酶抑制剂（他汀类药物）是患有血脂血症患者中低密度脂蛋白胆固醇（LDL-C）通常处方的药物，并增加了CV风险。在一般的非HIV感染人群中，已证明他汀类药物对CV事件和死亡率的初级和次要预防具有疗效。在这些研究中，CV发病率的降低不能完全通过他汀类药物降低LDL-C水平的能力完全解释，并且已经假设这些药物的许多有益作用可能是由于该类别药物的抗炎特性所致。我们假设HAART的HIV人群的CV风险增加具有继发于未完全抑制HIV引起的慢性炎症的炎症成分，而他汀类药物可能在减少这种炎症方面具有功效。我们建议在中间简历风险的100名艾滋病毒受试者中评估低剂量阿托伐他汀对2年内简历风险的替代标记的影响；特别是其对肱动脉流动介导的血管舒张的影响，对电子束断层扫描的冠状动脉钙的沉积以及HS-CRP水平的变化。在这项临床试验中，我们建议评估Th17淋巴细胞及其分泌化合物白介素17在持续HIV引起的炎症过程中的作用，从而导致HAART患者的CV风险增加。此外，我们建议评估HIV诱导的炎症过程对胰岛素抵抗以及氧化磷酸化酶和活性水平的影响。感染HIV的个体可能有心血管（CV）疾病的高风险。我们建议建立150名患者队列，以将氧化应激和炎症的作用视为这种高CV风险的原因。此外，我们提出了一项针对50名来自队列的患者的美伐伐汀（一种脂质降低药物）的小型临床试验，该试验具有炎症的证据（血液中高C反应性蛋白水平），但胆固醇水平较低，以查看此类药物的抗炎特性是否会降低CV风险。 （抽象的结尾）