title: The mitochondria-targeted antioxidant MitoQ attenuates liver fibrosis in mice.
abstract: Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis.
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South CarolinaCharleston, SC 29425, USA; Department of Biology, Faculty of Sciences, University of TabukSaudi Arabia.
authors.forename: Hasibur
authors.initials: H
authors.lastname: Rehman
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South CarolinaCharleston, SC 29425, USA; The Second Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning Province, China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina Charleston, SC 29425, USA.
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Krishnasamy
authors.affiliation: Department of Medicine, Medical University of South Carolina Charleston, SC 29425, USA.
authors.forename: Zengdun
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina Charleston, SC 29425, USA.
authors.forename: Venkat K
authors.initials: VK
authors.lastname: Ramshesh
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina Charleston, SC 29425, USA.
authors.forename: Khujista
authors.initials: K
authors.lastname: Haque
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South CarolinaCharleston, SC 29425, USA; Ralph H. Johnson VA Medical CenterCharleston, SC 29403, USA.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building Cambridge CB2 0XY, U.K.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South CarolinaCharleston, SC 29425, USA; Department of Biochemistry & Molecular Biology, Medical University of South CarolinaCharleston, SC 29425, USA; Institute of Theoretical & Experimental Biophysics, Russian Academy of SciencesPushchino, Russian Federation.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.affiliation: Department of Medicine, Medical University of South Carolina Charleston, SC 29425, USA.
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina Charleston, SC 29425, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhong
keywords: Antioxidant; MitoQ; hepatic stellate cell; liver fibrosis; mitochondria; oxidative stress