Sirtuin 1 represses PKC-ζ activity through regulating interplay of acetylation and phosphorylation in cardiac hypertrophy.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
07
05
2018
revised:
20
09
2018
accepted:
17
10
2018
pubmed:
11
11
2018
medline:
25
2
2020
entrez:
11
11
2018
Statut:
ppublish
Résumé
Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-ζ was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo. Overexpression of PKC-ζ led to cardiac hypertrophy and increased activity of NF-κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-ζ, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy. Sirtuin1 is an endogenous negative regulator for PKC-ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.
Sections du résumé
BACKGROUND AND PURPOSE
Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy.
EXPERIMENTAL APPROACH
Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-ζ was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo.
KEY RESULTS
Overexpression of PKC-ζ led to cardiac hypertrophy and increased activity of NF-κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-ζ, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy.
CONCLUSIONS AND IMPLICATIONS
Sirtuin1 is an endogenous negative regulator for PKC-ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.
Identifiants
pubmed: 30414383
doi: 10.1111/bph.14538
pmc: PMC6329629
doi:
Substances chimiques
protein kinase C zeta
EC 2.7.11.1
Protein Kinase C
EC 2.7.11.13
Sirtuin 1
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
416-435Informations de copyright
© 2018 The British Pharmacological Society.
Références
J Biol Chem. 2012 Mar 2;287(10):7792-802
pubmed: 22232556
Mol Cell Biochem. 2007 Nov;305(1-2):103-11
pubmed: 17594058
Br J Pharmacol. 2017 Dec;174 Suppl 1:S272-S359
pubmed: 29055034
Curr Biol. 1998 Sep 24;8(19):1069-77
pubmed: 9768361
Blood Press. 2010 Jun;19(3):196-205
pubmed: 20429690
J Clin Invest. 1997 Nov 1;100(9):2189-95
pubmed: 9410895
Biochim Biophys Acta. 2016 Dec;1863(12):3027-3039
pubmed: 27686254
Br J Pharmacol. 2007 Sep;152(2):169-71
pubmed: 17592504
J Nutr Metab. 2018 Feb 1;2018:8547976
pubmed: 29484207
Can J Cardiol. 2016 May;32(5):634-41
pubmed: 26948035
Cardiovasc Res. 2011 May 1;90(2):276-84
pubmed: 21115502
Biochem Pharmacol. 2017 May 15;132:102-117
pubmed: 28237649
Nat Med. 2012 Nov;18(11):1617-9
pubmed: 23135512
J Pharmacol Sci. 2016 Sep;132(1):15-23
pubmed: 27094369
J Biol Chem. 2007 Mar 2;282(9):6823-32
pubmed: 17197703
Heart Fail Rev. 2017 Nov;22(6):843-859
pubmed: 28702857
FEBS Lett. 1994 Dec 19;356(2-3):275-8
pubmed: 7805853
Cardiovasc Res. 2009 May 1;82(2):229-39
pubmed: 19168855
Br J Pharmacol. 2019 Feb;176(3):416-435
pubmed: 30414383
Atherosclerosis. 2017 Oct;265:275-282
pubmed: 28870631
Drug Discov Today Dis Mech. 2010 Summer;7(2):e87-e93
pubmed: 21151743
J Am Coll Cardiol. 1998 Nov;32(5):1454-9
pubmed: 9809962
Nature. 2009 Jul 30;460(7255):587-91
pubmed: 19641587
Br J Pharmacol. 2018 Apr;175(7):987-993
pubmed: 29520785
Biomed Pharmacother. 2017 Jun;90:386-392
pubmed: 28380414
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
EMBO J. 1995 Dec 15;14(24):6157-63
pubmed: 8557035
Br J Pharmacol. 2017 Dec;174 Suppl 1:S1-S16
pubmed: 29055037
Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
pubmed: 16936699
Free Radic Biol Med. 2013 Dec;65:528-540
pubmed: 23891678
Biochem Biophys Res Commun. 2008 Oct 3;374(4):641-6
pubmed: 18662671
Physiology (Bethesda). 2012 Jun;27(3):130-9
pubmed: 22689788
Eur Heart J. 2017 May 7;38(18):1389-1398
pubmed: 27099261
Br J Pharmacol. 2013 Jan;168(1):117-28
pubmed: 22335191
Br J Pharmacol. 2018 Apr;175(8):1126-1145
pubmed: 28503736
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
J Cell Mol Med. 2012 Jan;16(1):83-95
pubmed: 21418519
Cardiovasc Drugs Ther. 2002 May;16(3):245-9
pubmed: 12374903
Br J Pharmacol. 2015 Jun;172(11):2852-63
pubmed: 25625556
Mol Cell Biol. 2003 Jan;23(1):38-54
pubmed: 12482959
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9
pubmed: 12960381
J Biol Chem. 2007 Apr 27;282(17):12450-7
pubmed: 17308302
Biomol Concepts. 2017 Sep 26;8(3-4):143-153
pubmed: 28841566
Transl Res. 2015 Nov;166(5):459-473.e3
pubmed: 26118953
J Biochem. 2003 Jan;133(1):1-7
pubmed: 12761192
Pharmacol Res. 2010 Nov;62(5):365-83
pubmed: 20643208
Biochem Biophys Res Commun. 2013 Jan 18;430(3):944-50
pubmed: 23261455
Circ Res. 2007 May 25;100(10):1512-21
pubmed: 17446436
J Clin Invest. 2009 Sep;119(9):2758-71
pubmed: 19652361
Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1804-14
pubmed: 18245565
Mol Cell. 2001 Oct;8(4):771-80
pubmed: 11684013
J Proteome Res. 2006 Nov;5(11):2901-8
pubmed: 17081041
Br J Pharmacol. 2015 Jul;172(13):3189-93
pubmed: 25964986
Science. 1998 Sep 25;281(5385):2042-5
pubmed: 9748166