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

基本信息

批准号：
7881415
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
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7881415
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 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 Patients Pharmaceutical Preparations Pharmacotherapy Production Protease Inhibitor 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 Wild Type Mouse Work Zidovudine antiretroviral therapy atherogenesis catalase cytokine design in vivo inhibitor/antagonist isoprostaglandin F2alpha type-III mitochondrial dysfunction mouse model overexpression prevent receptor research study response treatment duration vascular smooth muscle cell proliferation

项目摘要

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艾滋病毒治疗的主要并发症。尽管大量临床试验检查了动脉粥样硬化与HIV感染或HIV的抗逆转录病毒治疗之间的关系，但尚未观察到确切的因果关系。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，以研究抗逆转录病毒（ART）对血管内皮功能的影响。动脉粥样硬化是动脉壁中以胆固醇斑块形成为特征的疾病，是由内皮损伤引发的，导致细胞因子和生长因子的释放。这些生长因子促进了许多永久性事件，例如血管平滑肌细胞（VSMC）增殖，它们在动脉粥样硬化病变的形成下达到顶点。因此，内皮功能障碍是一个早期事件，已显示为动脉粥样硬化的敏感标志物。在我们使用两种啮齿动脉粥样硬化模型的最初研究中，ART在治疗后的5天内诱导了剧烈的内皮功能障碍，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了活性氧（ROS）的产生和有丝分裂因子内皮素-1（ET-1）的释放。尽管这些药物仅对VSMC没有明显的影响，但在VSMC和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通过在血管内皮中诱导线粒体功能障碍来启动或加剧动脉粥样硬化。使用血管细胞的共培养系统和我们的小鼠模型进行动脉粥样硬化，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贡献，2）反应性氧在Art介导的内皮功能障碍和ET-ET-Indists中的反应性氧的贡献，以及Artistife the Artistive，以及3）Artist-end Artistim- 3）ARTISIS-ENDINS-ELDISS IND-ARTISTILISS ETHILIDER-3）肌肉细胞增殖。局部摘要：心血管疾病现在被认为是HIV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与HIV相关的心血管疾病的原因。因此，拟议的工作将在设计方法以更好地治疗艾滋病毒感染者的方式方面具有临床益处。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment.

DOI：
10.1093/toxsci/kft105
发表时间：
2013-08
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
0
作者：
Stephen Y. Xue;Valeria Y. Hebert;Danicia M Hayes;Corie N Robinson;Mitzi C. Glover;T. Dugas
通讯作者：
Stephen Y. Xue;Valeria Y. Hebert;Danicia M Hayes;Corie N Robinson;Mitzi C. Glover;T. Dugas