title: Efavirenz Causes Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Endothelial Cells.
abstract: The non-nucleoside reverse transcriptase inhibitor efavirenz is a widely prescribed antiretroviral drug used in combined antiretroviral therapy. Despite being an essential and life-saving medication, the required lifelong use of HIV drugs has been associated with a variety of adverse effects, including disturbances in lipid metabolism and increased cardiovascular risk. Efavirenz belongs to those HIV drugs for which cardiovascular and endothelial dysfunctions have been reported. It is here shown that elevated concentrations of efavirenz can inhibit endothelial meshwork formation on extracellular matrix gels by normal and immortalized human umbilical vein cells. This inhibition was associated with an increase in oxidative stress markers, endoplasmic reticulum (ER) stress markers, and autophagy. Induction of ER stress occurred at pharmacologically relevant concentrations of efavirenz and resulted in reduced proliferation and cell viability of endothelial cells, which worsened in the presence of elevated efavirenz concentrations. In combination with the HIV protease inhibitor nelfinavir, both oxidative stress and ER stress became elevated in endothelial cells. These data indicate that pharmacologically relevant concentrations of efavirenz can impair cell viability of endothelial cells and that these effects may be aggravated by either elevated concentrations of efavirenz or by a combined use of efavirenz with other oxidative stress-inducing medications.
authors: Molecular Biology Laboratory, Ludwig-Maximilians-University, Munich, Germany.
authors: Marlene
authors: M
authors: Weiß
authors: Molecular Biology Laboratory, Ludwig-Maximilians-University, Munich, Germany.
authors: Bernd
authors: B
authors: Kost
authors: Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors: Ingrid
authors: I
authors: Renner-Müller
authors: Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University, Munich, Germany.
authors: Eckhard
authors: E
authors: Wolf
authors: Molecular Biology Laboratory, Ludwig-Maximilians-University, Munich, Germany.
authors: Ioannis
authors: I
authors: Mylonas
authors: Molecular Biology Laboratory, Ludwig-Maximilians-University, Munich, Germany. ansgar.bruening@med.uni-muenchen.de.|Molecular Biology Laboratory, University Hospital Munich, Maistrasse 11, 80337, Munich, Germany. ansgar.bruening@med.uni-muenchen.de.
authors: Ansgar
authors: A
authors: Brüning
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000633:toxicity*; D001343:Autophagy / Q000187:drug effects*; D048588:Benzoxazines / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000473:pathology; D019888:Nelfinavir / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019888:Nelfinavir; C098320:efavirenz
keywords: Efavirenz; Endoplasmic reticulum stress; Endothelial cells; Nelfinavir; Oxidative stress