Effects of HAART drugs on endothelial dysfunction of pu*

描述(由申请者提供)：艾滋病毒相关性肺动脉高压的发病率在过去几年中已被认识到，而且频率越来越高。然而，这一严重并发症的病因和潜在的分子机制尚不清楚。最近的临床报道表明，高效抗逆转录病毒治疗(HAART)可能会增加HIV相关性肺动脉高压的发生率。我们的初步数据表明，一些HAART药物在体外可损害猪肺动脉内皮依赖性的血管松弛，减少内皮型一氧化氮合酶(ENOS)的表达，增加超氧阴离子的产生。此外，一些HAART药物还可增加内皮通透性和氧化应激，并降低人肺动脉内皮细胞(HPAECs)几种连接分子的表达。此外，人参皂苷RBL和银杏内酯A能有效阻断HAART药物诱导的内皮功能障碍。在这些研究的基础上，我们提出了我们的中心假设，即某些HAART药物可能通过独特的分子途径导致肺动脉内皮细胞功能障碍和氧化应激，而人参和银杏化合物可能有效地阻断HAART药物对肺动脉的这些不利影响。因此，我们建议进行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。 目的1研究HAART药物对猪和人肺动脉内皮细胞血管运动活性和eNOS系统的影响。我们将研究血管舒缩活性，eNOS的表达，信号转导途径，以及前列腺素和内皮素系统。 目的2研究HAART药物对内皮细胞通透性、连接结构和分子的影响。我们将研究内皮通透性、连接分子的表达、调节以及信号转导途径。 目的3研究HAART药物对猪和人肺动脉内皮细胞ROS系统的影响。我们将研究ROS产生的类型和分子来源，ROS产生和内部抗氧化酶的活性和基因表达。 目的4研究人参、银杏化合物对HAART药物诱导的猪和人肺动脉内皮细胞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能阻断一些HAART药物引起的血管舒缩功能障碍和通透性增加，以及氧化应激和相关基因的表达和调节。人参和银杏化合物与维生素C和维生素E在阻断HAART诱导的内皮功能障碍方面的差异将进行比较。 本研究将阐明HAART药物对肺内皮细胞作用的分子机制，为制定有效的防治HIV相关性肺动脉高压的策略提供有价值的信息。

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.