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.

由于抗逆转录病毒疗法（CART）导致的死亡率降低，心血管疾病具有 在感染HIV的患者中成为死亡的主要原因。因为几种抗逆转录病毒会引起胰岛素 抗药性和血脂异常，动脉粥样硬化疾病的风险增加已归因于 这些药物。但是，有证据表明未经治疗的HIV感染显着促进 未来心血管事件的风险。炎症和内皮细胞功能障碍是关键启动子 一般人群的动脉粥样硬化。 HIV感染患者的血管病变表明增加 白细胞粘附于内皮，单核细胞趋化剂蛋白-1（MCP-1）水平升高 和血管细胞粘附分子-1（VCAM-1）。在CART-NA ve患者中，这些粘合分子的水平 增加，内皮功能障碍是常见的。购物车仅部分降低了这些分子的水平， 仅部分恢复内皮功能。我们的新型初步数据表明抗炎药 五氧化氨基林（PTX）可能显着改善肱动脉的流介导的词典，这是体内测量 内皮功能，通过抑制白细胞募集和粘合剂，在受HIV感染的受试者中。使用 细胞模型，我们发现感染HIV的T细胞上调内皮MCP-1，并且PTX抑制了 MCP-1的内皮产生。我们将直接解决RFA-HL-08-003的具体目标，即 “在提议的 协作研究。在此应用中，我们将解决与HIV相关炎症的中心假设 诱导内皮细胞功能障碍用五氧化氨酸链替林逆转。我们的具体目的是（1）确定 戊昔丁素对HIV感染受试者内皮功能的影响和（2）分析体外 HIV和PTX调节内皮细胞激活和损伤的机制。我们将调查 PTX在治疗试验中改善与HIV相关的内皮功能障碍的效用。我们还将研究 HIV引起的内皮功能障碍的机制以及PTX使用我们的IN逆转此过程的能力 体外模型。这项研究既及时又具有重要意义，因为它将超越观察性临床 通过涉及治疗试验和机械研究来识别新因果关系的研究 炎症和内皮功能之间的关系和病理机制。如果五氧化氨酸是 发现在拟议的研究中有效地改善内皮功能，然后是这种廉价，安全和 可以在较大的试验中研究广泛的药物，以减少感染HIV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