title: Antiretrovirals induce endothelial dysfunction via an oxidant-dependent pathway and promote neointimal hyperplasia.
abstract: Human immunodeficiency virus-1 antiretroviral treatment is associated with an increased incidence of atherosclerosis. We hypothesized that antiretrovirals directly impair endothelial function after short-term exposure and that with chronic exposure, this dysfunction promotes a proliferative response, inducing neointimal hyperplasia, thus contributing to vascular lesion formation. To test this hypothesis, we treated mice with the nucleoside reverse transcriptase inhibitor azidothymidine (AZT), the protease inhibitor indinavir, or AZT + indinavir. Treatment with AZT or AZT + indinavir for 5 days impaired endothelium-dependent vessel relaxation. Though indinavir treatment alone did not alter vessel relaxation, it potentiated the impairment of endothelium-dependent relaxation induced by AZT. Coadministration of the antioxidant Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin attenuated antiretroviral-induced endothelial dysfunction, suggesting that oxidant production may have a causal role in the observed endothelial dysfunction. To test whether the antiretrovirals promote a proliferative response following endothelial dysfunction, we treated mice with antiretrovirals for 14 days and then induced a carotid endothelial injury. Two weeks later, we observed a dramatic increase in neointimal formation in all antiretroviral-treated animals, and the newly formed neointima was comprised mainly of proliferated smooth muscle cells. Although a functional endothelium surrounding the lesioned area and re-endothelialization across the area of injury is important in reducing proliferation in this model, we tested whether the neointimal hyperplasia was associated with endothelial dysfunction. Plasma levels of asymmetric dimethylarginine, a biomarker of endothelial dysfunction, increased after treatment with indinavir or AZT + indinavir. On the other hand, treatment with AZT or AZT + indinavir increased endothelial vascular cell adhesion molecule staining. We conclude that short-term treatment with antiretrovirals elicited a direct impairment in endothelial function, in part via an oxidant-dependent pathway. These antiretrovirals also exacerbated injury-induced vascular smooth muscle cell proliferation and neointimal hyperplasia, likely because of their inhibition of endothelial function.
authors.affiliation: Department of Pharmacology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Alok R
authors.initials: AR
authors.lastname: Khandelwal
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.forename: Valeria Y
authors.initials: VY
authors.lastname: Hebert
authors.forename: James J
authors.initials: JJ
authors.lastname: Kleinedler
authors.forename: James H
authors.initials: JH
authors.lastname: Zavecz
authors.forename: Weibin
authors.initials: W
authors.lastname: Shi
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
authors.forename: Tammy R
authors.initials: TR
authors.lastname: Dugas
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006965:Hyperplasia / Q000139:chemically induced; D019469:Indinavir / Q000633:toxicity*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000139:chemically induced*; D015215:Zidovudine / Q000633:toxicity*
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D015215:Zidovudine; D019469:Indinavir; C018524:N,N-dimethylarginine; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D001120:Arginine