Loss of genomic integrity induced by lysosphingolipid imbalance drives ageing in the heart.
Aging
/ genetics
Animals
Curcumin
/ chemistry
DNA Damage
/ drug effects
Energy Metabolism
Epigenesis, Genetic
Evolution, Molecular
Fundulidae
Gene Expression Profiling
Gene Expression Regulation
Genetic Variation
Genomic Instability
Genomics
/ methods
Histone Acetyltransferases
/ chemistry
Histone Deacetylase Inhibitors
/ chemistry
Histones
/ metabolism
Humans
Models, Molecular
Myocardium
/ metabolism
Myocytes, Cardiac
/ metabolism
Sphingolipids
/ metabolism
Sphingosine
/ analogs & derivatives
Structure-Activity Relationship
Vertebrates
/ genetics
DNA damage
dihydrosphingosine
genomic instability
histone modification
transcription
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
14
11
2018
revised:
31
01
2019
accepted:
15
02
2019
pubmed:
20
3
2019
medline:
1
5
2020
entrez:
20
3
2019
Statut:
ppublish
Résumé
Cardiac dysfunctions dramatically increase with age. Revealing a currently unknown contributor to cardiac ageing, we report the age-dependent, cardiac-specific accumulation of the lysosphingolipid sphinganine (dihydrosphingosine, DHS) as an evolutionarily conserved hallmark of the aged vertebrate heart. Mechanistically, the DHS-derivative sphinganine-1-phosphate (DHS1P) directly inhibits HDAC1, causing an aberrant elevation in histone acetylation and transcription levels, leading to DNA damage. Accordingly, the pharmacological interventions, preventing (i) the accumulation of DHS1P using SPHK2 inhibitors, (ii) the aberrant increase in histone acetylation using histone acetyltransferase (HAT) inhibitors, (iii) the DHS1P-dependent increase in transcription using an RNA polymerase II inhibitor, block DHS-induced DNA damage in human cardiomyocytes. Importantly, an increase in DHS levels in the hearts of healthy young adult mice leads to an impairment in cardiac functionality indicated by a significant reduction in left ventricular fractional shortening and ejection fraction, mimicking the functional deterioration of aged hearts. These molecular and functional defects can be partially prevented
Identifiants
pubmed: 30886000
pii: embr.201847407
doi: 10.15252/embr.201847407
pmc: PMC6446199
pii:
doi:
Substances chimiques
Histone Deacetylase Inhibitors
0
Histones
0
Sphingolipids
0
Histone Acetyltransferases
EC 2.3.1.48
Curcumin
IT942ZTH98
Sphingosine
NGZ37HRE42
safingol
OWA98U788S
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
Subventions
Organisme : NHLBI NIH HHS
ID : K01 HL135464
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES027595
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL133720
Pays : United States
Organisme : NIH HHS
ID : S10 OD020025
Pays : United States
Informations de copyright
© 2019 The Authors.
Références
Carcinogenesis. 2010 Oct;31(10):1787-93
pubmed: 20688834
Methods Mol Biol. 2015;1263:243-50
pubmed: 25618350
Cell. 2013 Jun 6;153(6):1194-217
pubmed: 23746838
Cell Stem Cell. 2016 Mar 3;18(3):341-53
pubmed: 26748419
Development. 2009 Sep;136(18):3131-41
pubmed: 19700617
Trends Biochem Sci. 2016 Aug;41(8):700-711
pubmed: 27283514
Anticancer Res. 2010 Jul;30(7):2881-4
pubmed: 20683027
Biochem Cell Biol. 2005 Jun;83(3):344-53
pubmed: 15959560
J Mol Cell Cardiol. 2015 Jun;83:21-31
pubmed: 25724723
Cardiovasc Res. 2017 Jun 1;113(7):725-736
pubmed: 28460026
Clin Cancer Res. 2017 Aug 15;23(16):4642-4650
pubmed: 28420720
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Basic Res Cardiol. 2013 Jul;108(4):361
pubmed: 23740219
Nature. 2011 Apr 14;472(7342):221-5
pubmed: 21346760
Nature. 2006 Jun 22;441(7096):1011-4
pubmed: 16791200
Biochem J. 1999 Feb 15;338 ( Pt 1):161-6
pubmed: 9931312
J Biol Chem. 2010 Sep 10;285(37):28553-64
pubmed: 20587414
Mol Cell Biol. 2007 Mar;27(6):2343-58
pubmed: 17242207
Elife. 2015 Dec 01;4:e08833
pubmed: 26623667
Circ Res. 2018 Sep 14;123(7):773-786
pubmed: 30355081
Int J Oncol. 2009 Oct;35(4):909-20
pubmed: 19724929
J Pharmacol Exp Ther. 2015 Oct;355(1):23-31
pubmed: 26243740
PLoS One. 2012;7(7):e41958
pubmed: 22860038
J Biol Chem. 2004 Dec 3;279(49):51163-71
pubmed: 15383533
Exp Biol Med (Maywood). 2002 May;227(5):345-53
pubmed: 11976405
Genes Dev. 2007 Jul 15;21(14):1790-802
pubmed: 17639084
Cell Stem Cell. 2013 Mar 7;12(3):275-84
pubmed: 23472869
Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12325-30
pubmed: 21746928
Science. 2009 Sep 4;325(5945):1254-7
pubmed: 19729656
Nat Commun. 2016 Oct 11;7:13087
pubmed: 27725641
Mol Cell. 2013 Jul 11;51(1):57-67
pubmed: 23791785
Cell. 2015 Dec 3;163(6):1539-54
pubmed: 26638078
Annu Rev Cell Dev Biol. 2012;28:719-41
pubmed: 23057748
Blood Cancer J. 2015 Oct 16;5:e357
pubmed: 26473529
Annu Rev Physiol. 2012;74:131-51
pubmed: 21888508
Nat Protoc. 2006;1(1):23-9
pubmed: 17406208
Cell. 2015 Dec 3;163(6):1527-38
pubmed: 26638077
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20164-9
pubmed: 24284169
J Chem Inf Model. 2011 Oct 24;51(10):2778-86
pubmed: 21919503
PLoS One. 2015 Oct 02;10(10):e0139588
pubmed: 26431201
Antioxid Redox Signal. 2012 Jun 15;16(12):1492-526
pubmed: 22229339
Nat Protoc. 2013 Apr;8(4):800-9
pubmed: 23538883
Nucleic Acids Res. 2015 Jul 1;43(W1):W251-7
pubmed: 25897128