Cardiac-specific deletion of GCN5L1 restricts recovery from ischemia-reperfusion injury.
Animals
Down-Regulation
/ genetics
Female
Free Radical Scavengers
/ metabolism
Gene Deletion
Humans
Male
Mice, Knockout
Middle Aged
Mitochondrial Proteins
/ deficiency
Models, Biological
Myocardial Reperfusion Injury
/ genetics
Myocardium
/ metabolism
Myocytes, Cardiac
/ metabolism
Nerve Tissue Proteins
/ deficiency
Organ Specificity
Oxidative Stress
Reactive Oxygen Species
/ metabolism
Recovery of Function
ERK1/2
Ex vivo working heart
GCN5L1
Ischemia reperfusion
Reactive oxygen species
Journal
Journal of molecular and cellular cardiology
ISSN: 1095-8584
Titre abrégé: J Mol Cell Cardiol
Pays: England
ID NLM: 0262322
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
03
01
2019
revised:
31
01
2019
accepted:
14
02
2019
pubmed:
19
2
2019
medline:
23
6
2020
entrez:
19
2
2019
Statut:
ppublish
Résumé
GCN5L1 regulates mitochondrial protein acetylation, cellular bioenergetics, reactive oxygen species (ROS) generation, and organelle positioning in a number of diverse cell types. However, the functional role of GCN5L1 in the heart is currently unknown. As many of the factors regulated by GCN5L1 play a major role in ischemia-reperfusion (I/R) injury, we sought to determine if GCN5L1 is an important nexus in the response to cardiac ischemic stress. Deletion of GCN5L1 in cardiomyocytes resulted in impaired myocardial post-ischemic function and increased infarct development in isolated work-performing hearts. GCN5L1 knockout hearts displayed hallmarks of ROS damage, and scavenging of ROS restored cardiac function and reduced infarct volume in vivo. GCN5L1 knockdown in cardiac-derived AC16 cells was associated with reduced activation of the pro-survival MAP kinase ERK1/2, which was also reversed by ROS scavenging, leading to restored cell viability. We therefore conclude that GCN5L1 activity provides an important protection against I/R induced, ROS-mediated damage in the ischemic heart.
Identifiants
pubmed: 30776374
pii: S0022-2828(19)30039-2
doi: 10.1016/j.yjmcc.2019.02.009
pmc: PMC6486843
mid: NIHMS1522142
pii:
doi:
Substances chimiques
BLOC1S1 protein, human
0
BLOC1S1 protein, mouse
0
Free Radical Scavengers
0
Mitochondrial Proteins
0
Nerve Tissue Proteins
0
Reactive Oxygen Species
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
69-78Subventions
Organisme : NHLBI NIH HHS
ID : K22 HL116728
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132917
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL132917
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL110849
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
Références
Proc Soc Exp Biol Med. 1978 Sep;158(4):658-62
pubmed: 151282
Am J Physiol Cell Physiol. 2004 Oct;287(4):C817-33
pubmed: 15355853
Cardiovasc Res. 2005 Feb 1;65(2):469-77
pubmed: 15639486
J Mol Cell Cardiol. 2005 Jul;39(1):133-47
pubmed: 15913645
Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3524-31
pubmed: 17906102
Cardiovasc Drugs Ther. 2009 Aug;23(4):327-31
pubmed: 19466533
Exp Biol Med (Maywood). 2009 Sep;234(9):1011-9
pubmed: 19546346
Apoptosis. 2010 Jun;15(6):669-78
pubmed: 20151195
Methodist Debakey Cardiovasc J. 2009;5(3):2-7
pubmed: 20308957
Biochem J. 2012 May 1;443(3):655-61
pubmed: 22309213
J Mol Cell Cardiol. 2012 Aug;53(2):233-9
pubmed: 22659291
Korean Circ J. 2012 Sep;42(9):600-5
pubmed: 23091504
Int J Mol Med. 2013 Oct;32(4):917-25
pubmed: 23912965
J Biol Chem. 2014 Jan 31;289(5):2864-72
pubmed: 24356961
Cardiovasc Res. 2014 Sep 1;103(4):485-97
pubmed: 24966184
J Mol Cell Cardiol. 2015 Jan;78:80-9
pubmed: 25281838
Toxicol In Vitro. 2015 Aug;29(5):953-61
pubmed: 25835517
Am J Physiol Heart Circ Physiol. 2016 Aug 1;311(2):H347-63
pubmed: 27261364
Circulation. 2017 Mar 7;135(10):e146-e603
pubmed: 28122885
Nat Cell Biol. 2017 Apr;19(4):341-351
pubmed: 28319092
Am J Physiol Heart Circ Physiol. 2017 Aug 1;313(2):H265-H274
pubmed: 28526709
Curr Biol. 2017 Sep 11;27(17):2569-2578.e4
pubmed: 28823680
Nat Commun. 2017 Sep 12;8(1):523
pubmed: 28900165
Cell. 2017 Nov 16;171(5):1110-1124.e18
pubmed: 29033128
Trends Cell Biol. 2018 May;28(5):346-355
pubmed: 29477615
J Biol Chem. 2018 Nov 16;293(46):17676-17684
pubmed: 30323061
J Cell Sci. 2018 Nov 20;131(22):
pubmed: 30333138