Endothelium-dependent relaxation is abnormal in arterial diseases including, atherosclerosis and hypertension. Our group has recently established that endothelium-dependent relaxation is altered in an AIDS transgenic mouse. Furthermore, antiretroviraI treatment exacerbates impaired endothelium-dependent relaxation of arteries from the AIDS TG. It is well known that increased levels of reactive oxygen species impair endothelium-dependent relaxation as a result of a reduction in nitric oxide bioavailability and alterations in eNOS function. Studies from several laboratories including our own indicate that both HIV-1proteins and antiretroviral therapy increase the levels of reactive oxygen species and impact on antioxidant defense systems. However, mechanisms underlying the generation of reactive oxygen species in AIDS are unknown. This proposal defines the subcellular mechanism(s) underlying endothelial reactive oxygen species generation by specific HIV-1 proteins and antiretroviral therapies and determines the consequences of this oxidative stress on endothelium-dependent relaxation and development and progression of atherosclerosis in AIDS. Cellular mechanisms are examined using endothelial cells infected with HIV-1 peptides using retroviral vectors and endothelial cells isolated from transgenic models. Transgenic mice with both generalized and endothelium-specific expression of HIV-1 are used to determine the impact of HIV-1 proteins in vivo and ex vivo. Treatment of mouse models and cellular preparations with antiretrovirals defines the contribution of HIV-1 therapeutics to EC dysfunction in AIDS. The expected findings are likely to provide important new insights into the significance of abnormal endothelium dependent relaxation in AIDS and AIDS atherogenesis. Possible therapeutic targets to ameliorate these effects will be investigated.
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