HAART Drugs Induce Oxidative Stress in Human Endothelial Cells and Increase Endothelial Recruitment of Mononuclear Cells: Exacerbation by Inflammatory Cytokines and Amelioration by Antioxidants

Abstract

Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of HIV-1-infected patients but is associated with significant side effects such as diabetes, atherosclerosis, and cardiovascular complications. Oxidative stress can disrupt endothelial homeostasis by dysregulating the balance between pro- and antiatherogenic factors. We hypothesized that chronic exposure to HAART results in endothelial oxidative stress and activation of mononuclear cell recruitment, an early event in atherosclerosis. We studied the effects of HAART drug combinations, consisting of zidovudine, a nucleoside reverse transcriptase inhibitor; efavirenz, a nonnucleoside reverse transcriptase inhibitor; and either of the two protease inhibitors (PIs), indinavir or nelfinavir, on human aortic endothelial cells (HAECs) by monitoring the following parameters: (1) generation of reactive oxygen species (ROS), (2) mono-nuclear cell (Jurkat or U-937) adhesion, and (3) expression of cell adhesion molecules (CAMs). HAART exposure increased ROS formation in HAECs. Exposure to PIs alone and in HAART combinations increased mononuclear cell adhesion to HAECs in a concentration-dependent manner. Mononuclear cell adhesion to HAART-exposed HAECs was significantly enhanced following acute (24-h) exposure to the inflammatory cytokines, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and was suppressed by the antioxidants N-ace-tylcysteine and glutathione. Exposure to HAART increased intercellular adhesion molecule-1 (ICAM-1) gene expression and concomitant exposure to TNF-alpha further increased ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and endothelial-leukocyte adhesion molecule cell surface protein levels. These studies indicate that chronic HAART exposure increases oxidative stress in endothelial cells and induces mononuclear cell recruitment, which may eventually precipitate the cardiovascular diseases observed in HIV-1+ individuals on antiretroviral therapy.

Relationship of Body Composition, Metabolic Status, Antiretroviral Use, and HIV Disease Factors to Endothelial Dysfunction in HIV-Infected Subjects

“…28 We were unable to confirm a role for the PI class in inducing endothelial dysfunction. Human data 8,[10][11][12] and experimental models [29][30][31][32][33] have implicated PIs as a cause of endothelial dysfunction. The mechanism appears to include impaired nitric oxide bioavailability.…”

Metabolic effects associated to the highly active antiretroviral therapy (HAART) in AIDS patients

“…The chronic exposure to HAART results in endothelial oxidative stress and activation of mononuclear cells recruitment, an early event in atherosclerosis [21].…”

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

“…Oxidative stress and mtDNA depletion have been the suggested mechanisms, particularly in CM. [33][34][35][36][37][38][39][40][41][42][43][44][45][46] They may be critical pathogenetically because reactive oxygen species (ROS) are produced abundantly in mitochondria when electron transport chain (ETC) activity is disrupted. [47][48][49] ROS are also known to damage ETC complexes cyclically leading to increased ROS (induced by AZT), impaired respiration and further increases in ROS production, etc.…”