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: 7339366
• 负责人: TAMMY R DUGAS
• 金额: $ 27.91万
• 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/7339366
• 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HIV的主要并发症。虽然大量的临床试验已经研究了动脉粥样硬化与HIV感染或HIV的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的复杂性及其在人类中的治疗。我们已经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胆固醇斑块形成为特征的疾病，其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，如血管平滑肌细胞（VSMC）增殖，最终形成动脉粥样硬化病变。因此，内皮功能障碍是一个早期事件，并已被证明是动脉粥样硬化形成的敏感标志物。在我们使用两种啮齿动物动脉粥样硬化模型的初步研究中，ART在治疗后5天内诱导了显着的内皮功能障碍，而长期治疗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并增加活性氧（ROS）的产生和促有丝分裂因子内皮素-1（ET-1）的释放。虽然药物对VSMC没有明显的作用，但在VSMC和内皮细胞的共培养物中，药物以依赖于ET-1受体活化的方式增加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启动或加剧动脉粥样硬化形成。使用血管细胞的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诱导的血管平滑肌细胞增殖的机制。概述：心血管疾病现在被认为是艾滋病患者的主要并发症。这些研究将有助于解决用于治疗HIV的药物疗法是否是这种HIV相关心血管疾病的原因。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效益。