Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice.
Animals
Apoptosis
/ drug effects
Biomarkers
Cardiomegaly
/ pathology
Disease Models, Animal
Echocardiography
Fibroblasts
Fibrosis
Heart Failure
/ diagnostic imaging
Immunohistochemistry
Male
Mice
Models, Biological
Myocardium
/ metabolism
Organophosphorus Compounds
/ pharmacology
Signal Transduction
Stress, Mechanical
Transforming Growth Factor beta
/ metabolism
Ubiquinone
/ analogs & derivatives
Ventricular Dysfunction, Left
/ diagnostic imaging
Ventricular Remodeling
Ascending aortic constriction
Cardiac remodeling
IncRNA
Mitoquinone
Redox signaling
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
10
11
2018
revised:
03
01
2019
accepted:
06
01
2019
pubmed:
15
1
2019
medline:
2
4
2019
entrez:
15
1
2019
Statut:
ppublish
Résumé
Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.
Identifiants
pubmed: 30641298
pii: S2213-2317(18)31062-0
doi: 10.1016/j.redox.2019.101100
pmc: PMC6330374
pii:
doi:
Substances chimiques
Biomarkers
0
Organophosphorus Compounds
0
Transforming Growth Factor beta
0
Ubiquinone
1339-63-5
mitoquinone
47BYS17IY0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101100Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL118067
Pays : United States
Organisme : NHLBI NIH HHS
ID : R21 HL127599
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133011
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG050886
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL121206
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
Références
Anal Chem. 2016 Oct 4;88(19):9862-9868
pubmed: 27620367
Cardiovasc Ther. 2018 Aug;36(4):e12436
pubmed: 29797660
Hypertension. 2005 Mar;45(3):438-44
pubmed: 15699441
Int J Vasc Med. 2016;2016:2459687
pubmed: 27144026
Am J Physiol Heart Circ Physiol. 2017 Dec 1;313(6):H1098-H1108
pubmed: 28822962
Circ Heart Fail. 2013 Sep 1;6(5):1067-76
pubmed: 23935006
Hypertension. 2009 Aug;54(2):322-8
pubmed: 19581509
Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H397-402
pubmed: 23709599
Int J Physiol Pathophysiol Pharmacol. 2016 Apr 25;8(1):14-27
pubmed: 27186319
Circ Res. 2008 Feb 29;102(4):488-96
pubmed: 18096818
Nature. 2014 Oct 2;514(7520):102-106
pubmed: 25119045
Clin Exp Pharmacol Physiol. 2015 Jan;42(1):33-40
pubmed: 25311547
Circulation. 2010 Dec 21;122(25):2727-35
pubmed: 21173361
Circ Res. 2016 Mar 18;118(6):1021-40
pubmed: 26987915
Am J Physiol Heart Circ Physiol. 2015 Mar 15;308(6):H651-63
pubmed: 25599572
J Invest Dermatol. 2002 Feb;118(2):211-5
pubmed: 11841535
Alcohol Clin Exp Res. 2014 Nov;38(11):2731-42
pubmed: 25421510
Sci Rep. 2016 Oct 06;6:34314
pubmed: 27708346
Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15565-70
pubmed: 20713697
Circ Heart Fail. 2009 Mar;2(2):138-44
pubmed: 19808329
Noncoding RNA Res. 2017 Apr 08;2(1):68-73
pubmed: 30159422
Circulation. 2013 Jul 23;128(4):388-400
pubmed: 23877061
Front Physiol. 2018 Apr 03;9:324
pubmed: 29666587
Circ Res. 2005 Oct 28;97(9):900-7
pubmed: 16179589
Int J Mol Sci. 2017 Mar 10;18(3):
pubmed: 28287427
Free Radic Biol Med. 2018 Mar;117:18-29
pubmed: 29421236
Methods Find Exp Clin Pharmacol. 2003 Mar;25(2):79-86
pubmed: 12731452
PLoS One. 2016 Feb 26;11(2):e0150236
pubmed: 26919721
J Clin Invest. 2011 Jun;121(6):2301-12
pubmed: 21537080
Genome Res. 2012 Sep;22(9):1775-89
pubmed: 22955988
Liver Int. 2010 Aug;30(7):1019-26
pubmed: 20492507
Curr Top Med Chem. 2013;13(3):270-82
pubmed: 23432060
J Mol Cell Cardiol. 2011 Nov;51(5):632-9
pubmed: 21645518
Redox Biol. 2015 Aug;5:163-168
pubmed: 25965144
Fibrogenesis Tissue Repair. 2012 Sep 03;5(1):15
pubmed: 22943504
Heart. 2007 Aug;93(8):903-7
pubmed: 16670100
J Physiol. 2017 Jun 15;595(12):4037-4050
pubmed: 28233323
Antioxid Redox Signal. 2013 Jan 20;18(3):250-8
pubmed: 22657737
J Clin Invest. 2009 Oct;119(10):3079-88
pubmed: 19741299
Am J Physiol. 1998 May;274(5):H1812-20
pubmed: 9612394
Exp Biol Med (Maywood). 2017 Mar;242(5):487-496
pubmed: 28056547
Biochem J. 2010 Nov 15;432(1):9-19
pubmed: 20825366
J Am Coll Cardiol. 2000 Mar 1;35(3):569-82
pubmed: 10716457
Pharm Res. 2011 Nov;28(11):2910-9
pubmed: 21786065
Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2181-90
pubmed: 21949114
EMBO J. 2011 Sep 30;30(21):4414-22
pubmed: 21964070
PLoS One. 2012;7(9):e44899
pubmed: 23028668
Ann N Y Acad Sci. 2010 Jul;1201:96-103
pubmed: 20649545
Redox Biol. 2014 Jan 20;2:267-72
pubmed: 24494202
Circ Res. 2011 Apr 1;108(7):837-46
pubmed: 21311045
J Allergy Clin Immunol. 2015 Sep;136(3):769-80
pubmed: 25828268
Cell. 2004 Feb 20;116(4):499-509
pubmed: 14980218
Cardiovasc Hematol Disord Drug Targets. 2013 Aug;13(2):165-72
pubmed: 23988004
J Clin Invest. 2017 Oct 2;127(10):3770-3783
pubmed: 28891814
Circ Res. 2014 Jan 17;114(2):266-82
pubmed: 24186967
Sci Transl Med. 2016 Feb 17;8(326):326ra22
pubmed: 26888430
Am J Respir Crit Care Med. 2016 Jul 1;194(1):84-96
pubmed: 26771871
Nature. 2009 Mar 12;458(7235):223-7
pubmed: 19182780
Cell Mol Life Sci. 2018 Jan;75(2):291-300
pubmed: 28913665
Circ Res. 2003 May 2;92(8):912-9
pubmed: 12676814
Circ Res. 2011 Feb 4;108(3):378-96
pubmed: 21293009
J Vis Exp. 2014 May 21;(87):
pubmed: 24894542
FASEB J. 2005 Jul;19(9):1088-95
pubmed: 15985532
Mol Cancer Res. 2018 Apr;16(4):567-579
pubmed: 29555893