EFFECT OF HIV PROTEASE INHIBITORS ON ENDOTHELIAL DYSFUNC

描述（改编自申请人摘要） 明确HIV蛋白酶抑制剂在内皮依赖性 血管舒张和内皮形态。 假设1：蛋白酶抑制剂 可能损害内皮依赖性血管舒张和内皮形态。 一 新的动脉培养灌注模型（C. Chen R 01）和恒河猴模型 （H.麦克卢尔R 01）的SHIV感染将允许分析血管收缩 内皮细胞形态和亚结构 依赖性松弛也将通过高分辨率超声检查进行测试， 接受和未接受治疗的人的肱动脉（J伦诺克斯 R01）。 2)为了确定HIV蛋白酶抑制剂对NO产生的影响， eNOS活性和表达。 假设2：蛋白酶抑制剂可能影响NO 产生、eNOS活性和表达。 研究将确定否 生成，eNOS活性，eNOS基因表达，细胞代谢，eNOS 在动脉培养和猕猴中， 模型（Chen，麦克卢尔. eNOS活性也将在人类中测量， 接受或不接受蛋白酶抑制剂，并且在存在或不存在蛋白酶抑制剂的情况下， 内皮功能障碍（伦诺克斯）。 3)为了确定艾滋病毒的影响， 蛋白酶抑制剂可产生超氧阴离子（O2），NADH氧化酶 活性和过氧亚硝酸盐形成。 假设3：蛋白酶抑制剂可能 影响O2产生、NADH氧化酶活性和过氧亚硝酸盐形成。 动脉灌注培养和内皮细胞培养的分析将 包括O2产生、NADH氧化酶活性、Cu/An SOD表达（Chen）。 Cu/SOD表达、过氧亚硝酸盐形成、脂质过氧化， 在猕猴（Chen/麦克卢尔）和人类（伦诺克斯）中测量。 4)发展 预防HIV蛋白酶通道相关内皮细胞感染的策略 功能障碍 假设4：给予L-精氨酸作为NO供体，或 维生素E和C作为O2的产生，体外NADH氧化酶活性（C Chen）， Cu/Zn-SOD表达、过氧亚硝酸盐形成和脂质过氧化，以及 猕猴和人中维生素C和维生素E的血浆水平（Chen/麦克卢尔， 伦诺克斯）;以及肱动脉超声检查结果的变化（伦诺克斯）。 合作应用（基础科学-C。临床科学-Jeffrey 伦诺克斯和非人灵长类动物-哈罗德麦克卢尔）提交。 统称 综合基础科学，非人类灵长类动物和人类的研究提供了一个 多学科方法来了解和预防蛋白酶 动脉相关血管并发症。

DESCRIPTION (Adapted from the applicant's abstract) To define the role of HIV protease inhibitors in endothelium-dependent vasorelaxation and endothelial morphology. Hypothesis 1: protease inhibitors may impair endothelium-dependent vasorelaxation and endothelial morphology. A novel artery culture perfusion model (C. Chen R01) and a rhesus macaque model (H. McClure R01) of SHIV infection will allow analysis of vessel contraction and relaxation, endothelial cell morphology and substructures Endothelium- dependent relaxation will also be tested by high-resolution ultrasonography of the brachial artery in humans receiving and not receiving therapy (J Lennox R01). 2) To determine the effect of HIV protease inhibitors on NO production, eNOS activity and expression. Hypothesis 2: protease inhibitors may affect NO production, eNOS activity and expression. Studies will determine NO production, eNOS activity, eNOS gene expression, cell metabolism, eNOS transcription rate, and eNOS mRNA stability in the artery culture and macaque models (Chen, McClure. eNOS activity will also be measured in humans either receiving or not receiving protease inhibitors, and in the presence of absence of endothelial dysfunction (Lennox). 3) To determine the effect of HIV protease inhibitors may superoxide anion (O2) production, NADH oxidase activity, and peroxynitrite formation. Hypothesis 3: protease inhibitors may affect on O2 production, NADH oxidase activity, and peroxynitrite formation. Analyses in artery perfusion culture and endothelial cell cultures will include O2 production, NADH oxidase activity, Cu/An SOD expression (Chen). Cu/SOD expression, peroxynitrite formation, lipid peroxidation, will be measured in macaques (Chen/McClure) and in humans (Lennox). 4) To develop strategies to prevent HIV protease inhibitor-associated endothelial dysfunction. Hypothesis 4: administration of L-arginine as an NO donor or vitamins E and C as O2 production, NADH oxidase activity in vitro (C Chen), Cu/Zn-SOD expression, peroxynitrite formation and lipid peroxidation, and plasma levels of vitamin C and vitamin E in macaques and humans (Chen/McClure, Lennox); and changes in brachial artery ultrasound findings (Lennox). Collaborative applications (Basic science-C. Chen; Clinical science-Jeffrey Lennox; and Non-human primates-Harold McClure) are submitted. Together, the integrated basic science, non-human primate and human investigations offer a multi disciplinary approach to the understanding and prevention of protease inhibitor-associated vascular complications.