Antiretroviral Therapy, Endothelial Dysfunction and Atherosclerosis

抗逆转录病毒治疗、内皮功能障碍和动脉粥样硬化

• 批准号: 7484166
• 负责人: TAMMY R DUGAS
• 金额: $ 25.64万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484166
• 关键词: Address; Anti-Retroviral Agents; Antioxidants; Arachidonic Acids; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; B-Lymphocytes; Binding; Blood Vessels; C57BL/6 Mouse; Cardiovascular Diseases; Cell Proliferation; Cells; Cholesterol; Chronic; Clinical; Clinical Trials; Coculture Techniques; Complex; Complication; Development; Diet; Disease; Disruption; Drug Combinations; Endothelial Cells; Endothelin A Receptor; Endothelin-1; Endothelium; Enzymes; Event; Fatty acid glycerol esters; Functional disorder; Generations; Growth Factor; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Hour; Human; In Vitro; Indinavir; Individual; Injury; Interleukin-2; Isoprostanes; Lesion; Mediating; Mitochondria; Modeling; Mus; Nature; Nitric Oxide Synthase; Nucleosides; Numbers; Patients; Pharmaceutical Preparations; Pharmacotherapy; Production; Protease Inhibitor; Protein Overexpression; Reactive Oxygen Species; Receptor Activation; Respiratory Chain; Reverse Transcriptase Inhibitors; Rodent Model; Scheme; Serum; Site; Smooth Muscle Myocytes; Testing; Thromboxane Receptor; Toxin; Transgenic Organisms; Vascular Endothelial Cell; Vascular Endothelium; Vascular System; Week; Wild Type Mouse; Work; Zidovudine; antiretroviral therapy; atherogenesis; catalase; cytokine; design; in vivo; inhibitor/antagonist; isoprostaglandin F2alpha type-III; mitochondrial dysfunction; mouse model; prevent; receptor; research study; response; treatment duration; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Cardiovascular disease is now considered a major complication in the treatment of HIV. While a large number of clinical trials have examined the relationship between atherosclerosis and either the HIV infection or the antiretroviral treatment of HIV, no definitive cause-effect relationships have been observed. This may be due to the complex nature of HIV and its treatment in humans. We have developed a less complicated model to investigate the effects of antiretrovirals (ART) on the function of the vascular endothelium. Atherosclerosis, a disease characterized by cholesterol-laden plaque formation within the artery wall, is initiated by endothelial injury that results in the release of cytokines and growth factors. These growth factors promote a number of perpetuating events, such as vascular smooth muscle cell (VSMC) proliferation, that culminate in the formation of an atherosclerotic lesion. Thus, endothelial dysfunction is an early event and has been shown a sensitive marker for atherogenesis. In our initial studies using two rodent models for atherosclerosis, ART induced dramatic endothelial dysfunction within 5 days of treatment and chronic treatment exacerbated atherosclerotic lesion development. In addition, in endothelial cells in culture, ART induced mitochondrial dysfunction and increased the production of both reactive oxygen species (ROS) and the release of the mitogenic factor endothelin-1 (ET-1). Though the drugs had no apparent effect on VSMC alone, in cocultures of VSMC plus endothelial cells, the drugs increased VSMC proliferation in a manner dependent upon ET-1 receptor activation. We thus hypothesize that ART initiates or exacerbates atherogenesis by inducing a mitochondrial dysfunction in the vascular endothelium. Using both coculture systems of vascular cells and our mouse models for atherosclerosis, we will determine: 1) the contribution of mitochondrial dysfunction in ART-mediated endothelial dysfunction, 2) the contribution of reactive oxygen species production in ART-mediated endothelial dysfunction and ET-1 release, and 3) the mechanism by which ART promotes endothelium-derived ET-1 -induced vascular smooth muscle cell proliferation. LAY SUMMARY: Cardiovascular disease is now considered a major complication in HIV patients. These studies will help to address whether the drug therapy used to treat HIV is the cause of this HIV-related cardiovascular disease. The proposed work will thus be of clinical benefit in devising ways in which to better treat HIV-infected individuals.

描述（由申请人提供）：心血管疾病现在被认为是治疗艾滋病毒的主要并发症。虽然大量临床试验已经检验了动脉粥样硬化与 HIV 感染或 HIV 抗逆转录病毒治疗之间的关系，但尚未观察到明确的因果关系。这可能是由于艾滋病毒及其在人类中的治疗的复杂性。我们开发了一个不太复杂的模型来研究抗逆转录病毒药物（ART）对血管内皮功能的影响。动脉粥样硬化是一种以动脉壁内富含胆固醇的斑块形成为特征的疾病，由导致细胞因子和生长因子释放的内皮损伤引发。这些生长因子促进许多永久性事件，例如血管平滑肌细胞（VSMC）增殖，最终导致动脉粥样硬化病变的形成。因此，内皮功能障碍是一个早期事件，并且已被证明是动脉粥样硬化形成的敏感标志。在我们使用两种动脉粥样硬化啮齿动物模型进行的初步研究中，ART 在治疗后 5 天内诱发了严重的内皮功能障碍，而长期治疗则加剧了动脉粥样硬化病变的发展。此外，在培养的内皮细胞中，ART 诱导线粒体功能障碍，增加活性氧 (ROS) 的产生和促有丝分裂因子内皮素-1 (ET-1) 的释放。尽管这些药物单独对 VSMC 没有明显影响，但在 VSMC 与内皮细胞的共培养中，这些药物以依赖于 ET-1 受体激活的方式增加了 VSMC 增殖。因此，我们假设 ART 通过诱导血管内皮线粒体功能障碍来引发或加剧动脉粥样硬化形成。使用血管细胞共培养系统和我们的动脉粥样硬化小鼠模型，我们将确定：1）线粒体功能障碍在 ART 介导的内皮功能障碍中的作用，2）活性氧产生在 ART 介导的内皮功能障碍和 ET-1 释放中的作用，3）ART 促进内皮源性 ET-1 诱导的血管平滑的机制 肌肉细胞增殖。简单总结：心血管疾病现在被认为是艾滋病毒患者的主要并发症。这些研究将有助于确定用于治疗艾滋病毒的药物疗法是否是这种与艾滋病毒相关的心血管疾病的原因。因此，拟议的工作将在设计更好地治疗艾滋病毒感染者的方法方面具有临床益处。