HIV, Inflammation, and Endothelial Dysfunction

HIV、炎症和内皮功能障碍

• 批准号: 8312485
• 负责人: Matthias Clauss
• 金额: $ 74.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312485
• 关键词: Address; Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Adhesion Molecules; Cell model; Cells; Clinical Research; Clinical Trials; Control Groups; Data; Disease; Dyslipidemias; Endothelial Cells; Endothelium; Enrollment; Event; Functional disorder; Future; General Population; Goals; HIV; HIV Infections; Immunologics; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Insulin Resistance; Interruption; Investigation; Knowledge; Laboratories; Lead; Lesion; Leukocytes; Matched Group; Measures; Mediating; Metabolic; Monocyte Chemoattractant Protein-1; Mononuclear; Pathologic; Pathway interactions; Patients; Pentoxifylline; Pharmaceutical Preparations; Population; Process; Production; Research; Resources; Risk; Structure; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Therapy Clinical Trials; Toxic effect; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; Viral Proteins; antiretroviral therapy; brachial artery; cardiovascular risk factor; clinical effect; cytokine; improved; in vitro Model; in vivo; mortality; novel; promoter; randomized placebo controlled trial

With the reduction in mortality due to combination antiretroviral therapy (cART), cardiovascular disease has emerged as a leading cause of death in HIV-infected patients. Because several antiretrovirals cause insulin resistance and dyslipidemia, the increased risk for atherosclerotic disease has been attributed primarily to these drugs. However, evidence is emerging that suggest untreated HIV infection contributes significantly to the risk for future cardiovascular events. Inflammation and endothelial cell dysfunction are key promoters of atherosclerosis in the general population. Vascular lesions in HIV-infected patients demonstrate increased leukocyte adhesion to the endothelium with elevated levels of monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1). In cART-na¿ve patients, levels of these adhesion molecules are increased and endothelial dysfunction is common. cART only partly reduces levels of these molecules and only partly restores endothelial function. Our novel preliminary data suggest that the anti-inflammatory drug pentoxifylline (PTX) may significantly improve flow-mediated dilation of the brachial artery, an in vivo measure of endothelial function, in HIV-infected subjects by inhibiting leukocyte recruitment and adhesion. Using a cellular model, we found that HIV-infected T cells upregulate endothelial MCP-1 and that PTX inhibits endothelial production of MCP-1. We will directly address a specific objective of RFA-HL-08-003, which is to "examine the direct effects of HIV itself on the endothelium and identify any mitigating factors" in the proposed collaborative studies. In this application, we will address the central hypothesis that HIV-related inflammation induces endothelial cell dysfunction that is reversed with pentoxifylline. Our Specific Aims are (1) To determine the effects of pentoxifylline on endothelial function in HIV-infected subjects and (2) To analyze in vitro mechanisms by which HIV and PTX modulate endothelial cell activation and injury. We will investigate the utility of PTX to improve HIV-related endothelial dysfunction in therapeutic trials. We will also study the mechanism of HIV-induced endothelial dysfunction and the ability of PTX to reverse this process using our in vitro models. This research is both timely and significant because it will move beyond observational clinical research by involving both therapeutic trials and mechanistic investigations to identify novel causal relationships and pathologic mechanisms between inflammation and endothelial function. If pentoxifylline is found to be effective in improving endothelial function in the proposed studies, then this inexpensive, safe, and widely available drug can be studied in larger trials to reduce cardiovascular endpoints in HIV-infected patients.

随着联合抗逆转录病毒治疗（cART）导致的死亡率降低，心血管疾病已 成为艾滋病毒感染者死亡的主要原因。因为几种抗逆转录病毒药物 抵抗和血脂异常，动脉粥样硬化疾病的风险增加主要归因于 这些药物。然而，新的证据表明，未经治疗的艾滋病毒感染大大有助于 未来心血管事件的风险。炎症和内皮细胞功能障碍是内皮细胞增殖的关键促进因素。 动脉粥样硬化在普通人群中。艾滋病毒感染者的血管病变增加 单核细胞趋化蛋白-1（MCP-1）水平升高时白细胞粘附于内皮 和血管细胞粘附分子-1（VCAM-1）。在cART初治患者中，这些粘附分子的水平 内皮功能障碍是常见的。cART仅部分降低这些分子的水平， 只能部分恢复内皮功能我们新的初步数据表明，这种抗炎药 戊氨酰茶碱（PTX）可显著改善肱动脉的血流介导的扩张， 通过抑制白细胞募集和粘附，在HIV感染者中改善内皮功能。使用 在细胞模型中，我们发现HIV感染的T细胞上调内皮MCP-1，PTX抑制内皮MCP-1的表达。 内皮细胞产生MCP-1。我们将直接讨论RFA-HL-08-003的具体目标，即 “检查艾滋病毒本身对内皮细胞的直接影响，并确定任何缓解因素”， 合作研究。在这个应用程序中，我们将解决的核心假设，艾滋病毒相关的炎症 诱导内皮细胞功能障碍，其可被戊氨酰茶碱逆转。我们的具体目标是（1）确定 戊氨酰茶碱对HIV感染者内皮功能的影响;（2）体外分析 HIV和PTX调节内皮细胞活化和损伤的机制。我们将调查 PTX在治疗试验中改善HIV相关内皮功能障碍的效用我们亦会研究 HIV诱导的内皮功能障碍的机制和PTX逆转这一过程的能力， 体外模型这项研究既及时又重要，因为它将超越观察性临床 通过涉及治疗试验和机制研究来确定新的因果关系 炎症和内皮功能之间的关系和病理机制。如果喷替福林是 在拟议的研究中发现有效改善内皮功能，那么这种便宜，安全， 广泛使用的药物可以在更大的试验中进行研究，以减少艾滋病毒感染患者的心血管终点。

项目成果

Effects of switching from efavirenz to raltegravir on endothelial function, bone mineral metabolism, inflammation, and renal function: a randomized, controlled trial.

• DOI: 10.1097/qai.0b013e3182a97c39
• 发表时间: 2013-11-01
• 期刊: Journal of acquired immune deficiency syndromes (1999)
• 作者: Gupta SK;Mi D;Moe SM;Dubé MP;Liu Z
• 通讯作者: Liu Z

Increased cardiovascular disease risk in the HIV-positive population on ART: potential role of HIV-Nef and Tat.

接受 ART 的 HIV 阳性人群心血管疾病风险增加：HIV-Nef 和 Tat 的潜在作用。

• DOI: 10.1016/j.carpath.2015.07.001
• 发表时间: 2015
• 期刊: Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology
• 作者: Wang,Ting;Yi,Ru;Green,LindenAnn;Chelvanambi,Sarvesh;Seimetz,Michael;Clauss,Matthias
• 通讯作者: Clauss,Matthias