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.

Roles and Mechanisms of Human Immunodeficiency Virus Protease Inhibitor Ritonavir and Other Anti-Human Immunodeficiency Virus Drugs in Endothelial Dysfunction of Porcine Pulmonary Arteries and Human Pulmonary Artery Endothelial Cells

“…Most recently, an in vivo study reported that AZT or AZT plus indinavir treatments dramatically reduced endothelium-dependent vessel relaxation in aortic rings of rats. 24 Our current study demonstrated, for the first time, several individual HAART drugs and the combination of three drugs could induce vasomotor dysfunction in porcine pulmonary arteries, which may suggest a mechanism of HIV-PAH.…”

Role of Mitochondria in HIV Infection and Associated Metabolic Disorders: Focus on Nonalcoholic Fatty Liver Disease and Lipodystrophy Syndrome

“…Thus, AZT inhibits the mitochondrial adenylate kinase and adenosine nucleotide translocator in isolated mitochondria [19]. AZT also promotes oxidative stress (OS) and exerts a direct inhibitory effect on the electron transport chain, thereby diminishing OXPHOS [21, 22]. NRTIs also induce a significant reduction in complex IV activity and a specific inhibition of complex I [21, 23, 24].…”

Endothelial Dysfunction in HIV

“…Another study showed that Gp120 significantly increased the expression of human endothelial intercellular adhesion molecules (ICAM-1) at both m-RNA and protein levels, although it did not alter expression of VCAM-1 and E-selectin (Ren et al, 2002). Furthermore, Gp120 has been shown to significantly reduce eNOS expression and endothelium dependent vasorelaxation in porcine and coronary arteries pre-treated with TNF-α; the authors also demonstrated that the combination of Gp120 and TNF-α substantially up-regulated ICAM-1 expression in these arteries (Jiang et al, 2010). In a different study the same authors showed that the HIV viral proteins Tat and Nef could also inhibit eNOS expression in endothelial cells.…”

“…As with other chronic insults, ART-induced endothelial dysfunction may progress to established vascular disease over time. A study by Jiang et al showed that short term treatment (five days) of mice with AZT resulted in a reduction in endothelium-dependent vessel relaxation; however after two weeks of treatment the authors showed a significant increase in injury-induced vascular smooth muscle proliferation and neo-intimal hyperplasia (Jiang et al, 2010). In the same study the authors demonstrated that this increase in neo-intimal hyperplasia correlated with an increase in vascular cell adhesion molecule staining, providing a link between ART and induction of cell adhesion molecules.…”