EFFECT OF HIV PROTEASE INHIBITORS ON ENDOTHELIAL DYSFUNC

描述(改编自申请人的摘要) 明确HIV蛋白水解酶抑制剂在内皮依赖性中的作用 血管松弛和内皮细胞形态。假设1：蛋白酶抑制剂 可能损害内皮依赖的血管松弛和内皮细胞的形态。一个 一种新的动脉培养灌流模型和恒河猴模型 (H.McClure R01)的SIV感染将允许分析血管收缩 和松弛，内皮细胞形态和亚结构内皮- 依赖松弛也将通过高分辨率超声检查 接受和不接受治疗的人类的臂动脉(J Lennox R01)。2)为了确定HIV蛋白酶抑制剂对NO产生的影响， ENOS活性及表达。假设2：蛋白酶抑制剂可能影响NO 内皮型一氧化氮合酶活性及表达。研究将确定不 生产，eNOS活性，eNOS基因表达，细胞代谢，eNOS 动脉培养和猕猴的转录速率和eNOS基因的稳定性 模特(陈、麦克卢尔。ENOS的活性也将在人类身上进行测量。 接受或不接受蛋白酶抑制剂，以及在不存在的情况下 内皮功能障碍(Lennox)。3)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 活性和过氧亚硝酸根的形成。假设3：蛋白水解酶抑制剂可能 对O2产生、NADH氧化酶活性和过氧亚硝酸盐形成的影响。 动脉灌注培养和内皮细胞培养中的分析将 包括O2产生、NADH氧化酶活性、铜/AN超氧化物歧化酶表达(Chen)。 铜/超氧化物歧化酶的表达，过氧亚硝酸盐的形成，脂质过氧化 在猕猴(Chen/McClure)和人类(Lennox)中进行测量。4)大力发展 预防HIV蛋白水解酶抑制物相关内皮细胞的策略 功能障碍。假设4：L-精氨酸作为NO供体或 维生素E和C产生O2，体外NADH氧化酶活性(C Chen)， 铜/锌-超氧化物歧化酶的表达、过氧化亚硝酸盐的形成和脂质过氧化 猕猴和人类的血浆维生素C和维生素E水平(Chen/McClure， Lennox)；以及臂动脉超声检查结果的变化(Lennox)。 协作应用(基础科学-C。临床科学--杰弗里 和非人类灵长类--哈罗德·麦克卢尔)。团结在一起， 综合基础科学、非人类灵长类动物和人类研究提供了 从多学科角度认识和预防蛋白酶 与抑制剂相关的血管并发症。

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.