title: Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice.
abstract: Mitochondrial dysfunctions occur in many diseases linked to the systemic inflammatory response syndrome (SIRS). Mild uncoupling of oxidative phosphorylation is known to rescue model animals from pathologies related to mitochondrial dysfunctions and overproduction of reactive oxygen species (ROS). To study the potential of SIRS therapy by uncoupling, we tested protonophore dinitrophenol (DNP) and a free fatty acid (FFA) anion carrier, lipophilic cation dodecyltriphenylphosphonium (C12TPP) in mice and in vitro models of SIRS. DNP and C12TPP prevented the body temperature drop and lethality in mice injected with high doses of a SIRS inducer, tumor necrosis factor (TNF). The mitochondria-targeted antioxidant plastoquinonyl decyltriphenylphosphonium (SkQ1) which also catalyzes FFA-dependent uncoupling revealed similar protective effects and downregulated expression of the NFκB-regulated genes (VCAM1, ICAM1, MCP1, and IL-6) involved in the inflammatory response of endothelium in aortas of the TNF-treated mice. In vitro mild uncoupling rescued from TNF-induced endothelial permeability, disassembly of cell contacts and VE-cadherin cleavage by the matrix metalloprotease 9 (ММР9). The uncouplers prevented TNF-induced expression of MMP9 via inhibition of NFκB signaling. Water-soluble antioxidant Trolox also prevented TNF-induced activation and permeability of endothelium in vitro via inhibition of NFκB signaling, suggesting that the protective action of the uncouplers is linked to their antioxidant potential.
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Vlada V
authors.initials: VV
authors.lastname: Zakharova
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Olga Yu
authors.initials: OY
authors.lastname: Pletjushkina
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Ivan I
authors.initials: II
authors.lastname: Galkin
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zinovkin
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Chernyak
authors.affiliation: Department of Basic Medical Sciences, Ghent University, Ghent, Belgium; Molecular Signalling and Cell Death Unit, VIB-UGent Center for Inflammation Research and Department of Biomedical Molecular Biology, Ghent University.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Krysko
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent Belgium.
authors.forename: Claus
authors.initials: C
authors.lastname: Bachert
authors.affiliation: Upper Airways Research Laboratory, Ghent University, Ghent Belgium.
authors.forename: Olga
authors.initials: O
authors.lastname: Krysko
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Skulachev
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. Electronic address: k_popova_ch@mail.ru.
authors.forename: Ekaterina N
authors.initials: EN
authors.lastname: Popova
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002839:Chromans; D006571:Heterocyclic Compounds; D016328:NF-kappa B; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014475:Uncoupling Agents; C528765:tris(o-phenylenedioxy)cyclotriphosphazene; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: Endothelium; Mild uncoupling of oxidative phosphorylation; Mitochondria; Mitochondria-targeted antioxidant SkQ1