Effects of HIV drug combinations on endothelin-1 and vascular cell proliferation

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Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature involving endothelial and vascular smooth muscle cell (VSMC) proliferation, vasoconstriction, right ventricular hypertrophy, and eventually, right heart failure and death. PAH occurs 1000-fold more frequently in HIV patients than in the general population. Although conventional HIV therapy with nucleoside reverse transcriptase inhibitors (NRTIs) leads to regression of PAH, highly active antiretroviral therapy (HAART; two NRTI plus a protease inhibitor) increases the incidence of HIV-associated PAH as much as twofold. Although there are relatively few models for PAH, previous reports indicate the disease can be initiated by endothelial injury and release of the mitogen endothelin-1 (ET-1). ET-1, in turn, stimulates VSMC proliferation. To determine whether HAART induces endothelial injury and release of cytokines like ET-1, we treated human umbilical vein endothelial cells with micromolar amounts of AZT (3'-azido-3'-deoxythymidine), the protease inhibitor indinavir, or AZT plus indinavir, and measured cell viability, mitochondrial function, and ET-1 release. Both AZT and indinavir induced marked decreases in cellular oxygen uptake, as well as increases in ET-1 release. Although the drugs had no apparent effect on proliferation in VSMCs alone, in cocultures of VSMCs plus endothelial cells, the drugs increased proliferation of both endothelial cells and VSMCs. Finally, when cocultures of endothelial cells and VSMCs were treated with BQ-123 and BQ-788, selective antagonists for ET(A) and ET(B) receptors, respectively, drug-induced proliferation of both VSMCs and endothelial cells was attenuated. These data thus suggest that HIV drug cocktails may exacerbate preexisting HIV-associated PAH by inducing endothelial mitochondrial dysfunction, in turn stimulating the release of ET-1, and ultimately, vascular cell proliferation.

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Cardiovascular toxicology

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