HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants.
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.
Department of Pharmacology, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Debasis
D
Mondal
Leena
L
Pradhan
Mussa
M
Ali
Krishna C
KC
Agrawal
D000111:Acetylcysteine / Q000494:pharmacology; D000480:Alkynes; D000975:Antioxidants / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D048588:Benzoxazines; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D003521:Cyclopropanes; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000009:adverse effects; D007375:Interleukin-1 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D019888:Nelfinavir / Q000008:administration & dosage / Q000009:adverse effects; D010078:Oxazines / Q000008:administration & dosage / Q000009:adverse effects; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects
D000480:Alkynes; D000975:Antioxidants; D048588:Benzoxazines; D015815:Cell Adhesion Molecules; D003521:Cyclopropanes; D007375:Interleukin-1; D010078:Oxazines; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D015215:Zidovudine; D019469:Indinavir; D005978:Glutathione; D019888:Nelfinavir; C098320:efavirenz; D000111:Acetylcysteine