title: HAART drugs induce mitochondrial damage and intercellular gaps and gp120 causes apoptosis.
abstract: HIV-1 infection is associated with serious cardiovascular complications, but the roles of HIV-1, viral proteins, and highly active antiretroviral therapy (HAART) drugs are not understood. HAART decreases the overall risk of heart disease but leads to metabolic disturbances and possibly coronary artery disease. We investigated toxicities of HIV-1, HIV-1 glycoprotein 120 (gp120), and HAART drugs for human coronary artery endothelial cells (CAECs), brain microvascular endothelial cells, and neonatal rat ventricular myocytes (NRVMs). HIV-1 and gp120, but not azidothymidine (AZT), induced apoptosis of NRVMs and CAECs. Ethylisothiourea, an inhibitor of nitric oxide synthase, inhibited apoptosis induction by gp120. AZT, HIV-1, and gp120 all damaged mitochondria of cardiomyocytes. HAART drugs, AZT, and indinavir, but not HIV-1, produced intercellular gaps between confluent endothelial cells and decreased transendothelial electrical resistance. In conclusion, HIV-1 and gp120 induce toxicity through induction of cardiomyocyte and endothelial cell apoptosis. HAART drugs disrupt endothelial cell junctions and mitochondria and could cause vascular damage.
authors.affiliation: Department of Medicine, Greater Los Angeles VA Medical Center, Los Angeles, CA, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Fiala
authors.forename: Thomas
authors.initials: T
authors.lastname: Murphy
authors.forename: James
authors.initials: J
authors.lastname: MacDougall
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.forename: Alfonso
authors.initials: A
authors.lastname: Luque
authors.forename: Luisa
authors.initials: L
authors.lastname: Iruela-Arispe
authors.forename: John
authors.initials: J
authors.lastname: Cashman
authors.forename: Georgette
authors.initials: G
authors.lastname: Buga
authors.forename: Russel E
authors.initials: RE
authors.lastname: Byrns
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Barbaro
authors.forename: James
authors.initials: J
authors.lastname: Arthos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000633:toxicity; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology / Q000821:virology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D017629:Gap Junctions / Q000187:drug effects* / Q000473:pathology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015658:HIV Infections / Q000097:blood; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D019469:Indinavir / Q000633:toxicity*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D013890:Thiourea / Q000494:pharmacology; D015215:Zidovudine / Q000633:toxicity*
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D015699:HIV Envelope Protein gp120; D015215:Zidovudine; D019469:Indinavir; D013890:Thiourea