title: Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction.
abstract: The use of HIV protease inhibitors (PIs) has extended the duration and quality of life for HIV-positive individuals. However there is increasing concern that this antiviral therapy may promote premature cardiovascular disease by impairing endothelial cell (EC) function. In the present study, we investigated the effect of HIV PIs on EC function and determined if the enzyme heme oxygenase (HO-1) influences the biological action of these drugs. We found that three distinct PIs, including ritonavir, atazanavir, and lopinavir, stimulated the expression of HO-1 protein and mRNA. The induction of HO-1 was associated with an increase in NF-E2-related factor-2 (Nrf2) activity and reactive oxygen species (ROS). PIs also stimulated HO-1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. In addition, the PI-mediated induction of HO-1 was abolished by N-acetyl-l-cysteine and rotenone. Furthermore, PIs blocked EC proliferation and migration and stimulated the expression of intercellular adhesion molecule-1 and the adhesion of monocytes on ECs. Inhibition of HO-1 activity or expression potentiated the anti-proliferative and inflammatory actions of PIs which was reversed by bilirubin but not carbon monoxide. Alternatively, adenovirus-mediated overexpression of HO-1 attenuated the growth-inhibitory and inflammatory effect of PIs. In contrast, blocking HO-1 activity failed to modify the anti-migratory effect of the PIs. Thus, induction of HO-1 via the ROS-Nrf2 pathway in human ECs counteracts the anti-proliferative and inflammatory actions of PIs by generating bilirubin. Therapeutic approaches targeting HO-1 may provide a novel approach in preventing EC dysfunction and vascular disease in HIV-infected patients undergoing antiretroviral therapy.
authors.affiliation: Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Liu
authors.affiliation: Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA.
authors.forename: Zane E
authors.initials: ZE
authors.lastname: Durante
authors.affiliation: Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Peyton
authors.affiliation: Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO, USA. Electronic address: durantew@health.missouri.edu.
authors.forename: William
authors.initials: W
authors.lastname: Durante
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000009:adverse effects; D001663:Bilirubin / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage / Q000009:adverse effects; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects; D012402:Rotenone / Q000008:administration & dosage
chemical_list: D017320:HIV Protease Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D012402:Rotenone; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D051547:Heme Oxygenase-1; D019438:Ritonavir; D001663:Bilirubin; D000111:Acetylcysteine
keywords: Bilirubin; Carbon monoxide; Endothelial cells; HIV protease inhibitors; Heme oxygenase-1