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

Abstract

The objective of this study was to determine the effects of highly active antiretroviral therapy (HAART) drugs on pulmonary endothelial function. Porcine pulmonary arteries or human pulmonary arterial endothelial cells (HPAECs) were incubated with eight HAART drugs [ritonavir, indinavir, lopinavir, zidovudine (AZT), abacavir, stavudine, didanosine (ddI), and lamivudine] individually or in combination [three HAART drugs (3-plex; indinavir, stavudine, and ddI)] at their clinical plasma concentrations for 24 hours. Endothelium-dependent vasorelaxation in response to bradykinin was reduced significantly by the ritonavir in a concentration-dependent manner. Five other HAART drugs (indinavir, lamivudine, abacavir, AZT, and ddI) and the 3-plex significantly also impaired endothelium-dependent vasorelaxation in response to bradykinin. Five HAART drugs (ritonavir, indinavir, lamivudine, abacavir, and AZT) significantly decreased endothelial nitric oxide synthase (eNOS) expression and increased superoxide anion levels in both vessels and HPAECs. Furthermore, both ritonavir and AZT substantially activated ERK2 in HPAECs. Additionally, the antioxidants ginsenoside Rb1 and ginkgolide A effectively reversed HAART drug-induced vasomotor dysfunction and eNOS down-regulation. Inhibition of ERK1/2 also partially blocked ritonavir-and AZT-induced down-regulation of eNOS and vasomotor dysfunction. Thus, HAART drugs significantly impair endothelial functions of porcine pulmonary arteries and HPAECs, which may be mediated by eNOS down-regulation, oxidative stress, and ERK1/2 activation. These findings suggest that HAART drugs may contribute to the high incidence of pulmonary artery hypertension in human immunodeficiency virus-infected patients.

Efficacy of the CCR5 Antagonist Maraviroc in Reducing Early, Ritonavir-Induced Atherogenesis and Advanced Plaque Progression in Mice

“…Exposure to ritonavir increased the expression of CD36 and CCR5 on circulating monocytes and IL-17A release from spleen lymphocytes stimulated by concanavalin A and boosted the severe lipoatrophy of the epididymal fat with increased expression of IL-6. These results were consistent with several in vitro and ex vivo studies reporting direct toxicity of ritonavir on both endothelial cells [33][34][35] and human adipocytes, 36 as well as with recent observations in humans. 37 Lefevre et al 35 observed that long-term exposure to ritonavir of human coronary artery endothelial cells progressively induced endothelial dysfunction with an increased secretion of MCP-1, IL-6, ICAM-1, and VCAM-1.…”

Mg supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress, and cardiac dysfunction in rats

“…Since neutrophils are a major cellular source of free radical production, both its basal activation and NADPH oxidase upregulation might contribute significantly to systemic oxidative stress caused by RTV. Previous studies also reported that RTV administration resulted in endothelial toxicity associated with increased superoxide production in cultured cells and in isolated endothelium from RTV-treated animals (11,49). Consistent with elevated ROS generation from circulating PMNs, and likely from the endothelium, we observed significant elevations in plasma 8-isoprostane levels along with elevated RBC GSSG ratio; RBCs are constantly subjected to oxidative stress derived from the activated endothelium, especially when passing through the microvascular beds.…”

Effects of HIV Protease Inhibitors on Progression of Monocrotaline- and Hypoxia-Induced Pulmonary Hypertension in Rats

“…However, several HPIs, including ritonavir, have been reported to induce endothelial dysfunction in systemic arteries of HIV-infected patients and to diminish endothelium-dependent relaxation and endothelial nitric oxide expression in porcine pulmonary arteries and human pulmonary endothelial cells. 24 Because the expression and activity of eNOS are dependent on Akt signaling, the same pharmacological effects of HPIs may lead to 2 apparently opposite vascular effects: one exerted on endothelial cells and responsible for a decrease in eNOS activation with subsequent endothelial dysfunction, and the other exerted on PA-SMCs and responsible for inhibition of cell proliferation. Our results are consistent with this possibility.…”