1. Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice.
- Author
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Zakharova VV, Pletjushkina OY, Galkin II, Zinovkin RA, Chernyak BV, Krysko DV, Bachert C, Krysko O, Skulachev VP, and Popova EN
- Subjects
- Animals, Antioxidants pharmacology, Chromans pharmacology, Endothelium, Vascular pathology, Gene Expression Regulation drug effects, Mice, NF-kappa B metabolism, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Systemic Inflammatory Response Syndrome drug therapy, Systemic Inflammatory Response Syndrome pathology, Capillary Permeability drug effects, Endothelium, Vascular metabolism, Heterocyclic Compounds pharmacology, Organophosphorus Compounds pharmacology, Oxidative Phosphorylation drug effects, Systemic Inflammatory Response Syndrome metabolism, Tumor Necrosis Factor-alpha metabolism, Uncoupling Agents pharmacology
- 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 (C
12 TPP) in mice and in vitro models of SIRS. DNP and C12 TPP 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., (Copyright © 2017 Elsevier B.V. All rights reserved.)- Published
- 2017
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