1). 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 or absence of endothelial dysfunction (Lennox). 3). To determine the effect of HIV protease inhibitors on superoxide anion (O-2) production, NADH oxidase activity, and peroxynitrite formation. Hypothesis 3: protease inhibitors may affect on O-2 production, NADH oxidase activity, and peroxynitrite formation. Analyses in artery perfusion culture and endothelial cell cultures will include O-2. Scavengers may treat or prevent HIV protease inhibitor- associated endothelial dysfunction. Observations include vessel contraction and relaxation, NO release, eNOS activity and gene expression, O-2 production, NADH oxidase activity, Cu/Zn 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 O-2 scavengers may treat or prevent HIV protease inhibitor-associated endothelial dysfunction. Observations include vessel contraction and relaxation, No release, eNOG activity and gene expression, O-2 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.
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