Effects of HAART drugs on endothelial dysfunction of pu*

HAART药物对pu*内皮功能障碍的影响

• 批准号: 7123488
• 负责人: Changyi Chen
• 金额: $ 36.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123488
• 关键词: AIDS therapy; alternative medicine; antioxidants; antiviral agents; ascorbate; biological signal transduction; chemoprevention; endothelin; enzyme activity; free radical oxygen; gap junctions; gene expression; ginkgo biloba; human immunodeficiency virus; human tissue; nitric oxide synthase; oxidative stress; pharmacokinetics; prostaglandins; pulmonary hypertension; respiratory epithelium; swine; tissue /cell culture; tocopherols; vascular endothelium permeability; vasomotion

DESCRIPTION (provided by applicant): The incidence of HIV-related pulmonary hypertension has been recognized in the last few years with increasing frequency. However, the etiology and underlying molecular mechanisms of this serious complication are unknown. Recent clinical reports indicate that highly active antiretroviral therapy (HAART) may increase the incidence of HIV-related pulmonary hypertension. Our preliminary data have demonstrated that some HAART drugs impaired endothelium-dependent vasorelaxation, reduced the expression of endothelial nitric oxide synthase (eNOS), and increased super oxide anion production in porcine pulmonary arteries in vitro. In addition, some HAART drugs increased endothelial permeability and oxidative stress, and decreased the expression of several junctional molecules inhuman pulmonary artery endothelial cells (HPAECs). Furthetntore, ginsenoside Rbl and ginkgolide A effectively blocked some HAART drug-induced endothelial dysfunction. Based on these studies, we have developed our central hypotheses that some HAART drugs may cause endothelial dysfunction and oxidative stress in pulmonary arteries through unique molecular pathways, and ginseng and ginkgo compounds may effectively block these detrimental effects of HAART drugs on pulmonary arteries. Thus, we propose a multidisciplinary study to test these central hypotheses. Four specific aims are proposed. Aim 1 is designed to determine the effect of HAART drugs on vasomotor activities and the eNOS system in porcine pulmonary arteries and human pulmonary artery endothelial cells. We will investigate the vasomotor activities, eNOS expression, signal transduction pathways, and prostaglandin and endothelin systems. Aim 2 is designed to determine the effect of HAART drugs on endothelial permeability, junction structures, and molecules in human pulmonary artery endothelial cells. We will investigate endothelial permeability, junction molecular expression, and regulation as well as signal transduction pathways. Aim 3 is designed to determine the effect of HAART drugs on the reactive oxygen species (ROS) system in porcine pulmonary arteries and human pulmonary artery endothelial cells. We will investigate the types and molecular sources of ROS production, the activities and gene expression of ROS-generating and internal antioxidant enzymes. Aim 4 is designed to determine the effect of ginseng and ginkgo compounds on HAART drug induced-endothelial dysfunction and oxidative stress in porcine pulmonary arteries and human pulmonary artery endothelial cells. We will study whether ginseng and ginkgo compounds can block some HAART drug-induced vasomotor dysfunction and permeability increase as well as oxidative stress and related gene expression and regulation. The differences of ginseng and ginkgo compounds will be compared with vitamins C and E in blocking HAART-induced endothelial dysfunction. This study will elucidate the molecular mechanisms of HAART drugs' action on pulmonary endothelial cells and provide valuable information for the development of effective strategies for the prevention and treatment of HIV-related pulmonary hypertension.

描述（由申请人提供）：在过去的几年中，与HIV相关肺动脉高压的发生率随频率的增加而被识别。但是，这种严重并发症的病因和基本分子机制尚不清楚。最近的临床报告表明，高度活性的抗逆转录病毒疗法（HAART）可能会增加与HIV相关的肺动脉高压的发生率。我们的初步数据表明，某些HAART药物损害了内皮依赖性血管长期化，降低了内皮一氧化氮合酶（ENOS）的表达，并在体外的猪肺动脉中增加了超级氧化物阴离子的产生。此外，一些HAART药物增加了内皮渗透性和氧化应激，并降低了几个连接性分子非人类肺部动脉内皮细胞（HPAEC）的表达。除此之外，Ginsenoside RBL和Ginkgolide有效地阻断了一些HAART药物诱导的内皮功能障碍。基于这些研究，我们开发了我们的中心假设，即某些HAART药物可能通过独特的分子途径在肺动脉中引起内皮功能障碍和氧化应激，并且人参和银杏化合物可能有效地阻止了HAART药物对肺动脉群对HAART药物的这些有害作用。因此，我们提出了一项多学科研究来检验这些中心假设。提出了四个具体目标。 AIM 1旨在确定HAART药物对猪肺动脉和人肺动脉内皮细胞中血管舒缩活性和eNOS系统的影响。我们将研究血管舒缩活性，eNOS表达，信号转导途径以及前列腺素和内皮素系统。 AIM 2旨在确定HAART药物对人肺动脉内皮细胞中内皮渗透性，结构和分子的影响。我们将研究内皮渗透率，结分子表达和调节以及信号转导途径。 AIM 3旨在确定HAART药物对猪肺动脉和人肺动脉内皮细胞中活性氧（ROS）系统的影响。我们将研究ROS产生的类型和分子来源，ROS生成和内部抗氧化剂的活性和基因表达。 AIM 4旨在确定人参和银杏化合物对猪肺动脉和人肺动脉内皮细胞中HAART药物诱导的内皮功能障碍和氧化应激的影响。我们将研究人参和银杏化合物是否可以阻止某些HAART药物诱导的血管舒缩功能障碍和渗透性增加以及氧化应激以及相关的基因表达和调节。在阻断HAART诱导的内皮功能障碍时，将将人参和银杏化合物的差异与维生素C和E进行比较。 这项研究将阐明HAART药物对肺内皮细胞作用的分子机制，并为开发有效的策略提供预防和治疗HIV与HIV相关肺动脉高压的有效策略。