Soluble epoxide hydrolase deficiency attenuates lipotoxic cardiomyopathy via upregulation of AMPK-mTORC mediated autophagy.
AMPK-mTORC pathway
Autophagy
Cardiac lipid accumulation
Lipotoxic cardiomyopathy
Soluble epoxide hydrolase
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:
05 2021
05 2021
Historique:
received:
10
07
2020
revised:
13
12
2020
accepted:
15
12
2020
pubmed:
31
12
2020
medline:
1
12
2021
entrez:
30
12
2020
Statut:
ppublish
Résumé
Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6 J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. Palmitic acid (PA) was utilized to induce lipotoxicity to cardiomyocytes for in vitro study. We found sEH KO, independent of plasma lipid and blood pressures, significantly attenuated HFD-induced myocardial lipid accumulation and cardiac dysfunction in vivo. HFD-induced lipotoxic cardiomyopathy and dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin complex (AMPK-mTORC) signaling mediated lipid autophagy in heart were restored by sEH KO. In primary neonatal mouse cardiomyocytes, both sEH KO and sEH substrate EETs plus sEH inhibitor AUDA treatments attenuated PA-induced lipid accumulation. These effects were blocked by inhibition of AMPK or autophagy. The outcomes were supported by the results that sEH KO and EETs plus AUDA rescued HFD- and PA-induced impairment of autophagy upstream signaling of AMPK-mTORC, respectively. These findings revealed that sEH deficiency played an important role in attenuating myocardial lipid accumulation and provided new insights into treating lipotoxic cardiomyopathy. Regulation of autophagy via AMPK-mTORC signaling pathway is one of the underlying mechanisms.
Identifiants
pubmed: 33378686
pii: S0022-2828(20)30353-9
doi: 10.1016/j.yjmcc.2020.12.013
pmc: PMC8068623
mid: NIHMS1673572
pii:
doi:
Substances chimiques
Biomarkers
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
AMP-Activated Protein Kinases
EC 2.7.11.31
Epoxide Hydrolases
EC 3.3.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
80-91Subventions
Organisme : NIEHS NIH HHS
ID : P42 ES004699
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES030443
Pays : United States
Informations de copyright
Copyright © 2020. Published by Elsevier Ltd.
Références
Lipids. 2017 Sep;52(9):737-750
pubmed: 28825205
Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):536-41
pubmed: 25550510
Endocrine. 2013 Aug;44(1):87-98
pubmed: 23109223
Physiol Rep. 2014 Nov 20;2(11):
pubmed: 25413318
Autophagy. 2016;12(1):1-222
pubmed: 26799652
Trends Endocrinol Metab. 2016 Oct;27(10):696-705
pubmed: 27365163
Nat Genet. 2016 Sep;48(9):1049-1054
pubmed: 27455349
Nat Genet. 2008 May;40(5):529-37
pubmed: 18443590
N Engl J Med. 2002 Aug 1;347(5):305-13
pubmed: 12151467
Circ Res. 2018 Feb 2;122(3):489-505
pubmed: 29420210
Diabetes. 2010 Apr;59(4):997-1005
pubmed: 20068141
J Clin Invest. 2012 Nov;122(11):3919-30
pubmed: 23023704
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9038-43
pubmed: 21571638
Endocrinology. 2013 May;154(5):1743-53
pubmed: 23515292
EMBO Rep. 2013 Mar 1;14(3):242-51
pubmed: 23399656
J Vis Exp. 2013 Sep 06;(79):
pubmed: 24056408
Aging Cell. 2016 Oct;15(5):940-52
pubmed: 27416746
Adv Exp Med Biol. 2019;1206:85-108
pubmed: 31776981
PLoS One. 2014 Apr 08;9(4):e94400
pubmed: 24713619
Curr Vasc Pharmacol. 2013 Jan;11(1):105-11
pubmed: 22303912
Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5154-5159
pubmed: 30804206
Sci Rep. 2019 Nov 8;9(1):16327
pubmed: 31704980
Curr Opin Cell Biol. 2015 Apr;33:119-24
pubmed: 25703629
Acta Physiol (Oxf). 2018 Aug;223(4):e13074
pubmed: 29660243
Biochim Biophys Acta. 2015 Feb;1852(2):299-309
pubmed: 25018087
Cell Death Dis. 2013 Oct 24;4:e885
pubmed: 24157879
J Biol Chem. 2013 May 17;288(20):14189-14199
pubmed: 23576437
Nature. 2009 Apr 30;458(7242):1131-5
pubmed: 19339967
Obesity (Silver Spring). 2010 Mar;18(3):489-98
pubmed: 19644452
PLoS One. 2012;7(6):e39165
pubmed: 22720061
Crit Rev Biochem Mol Biol. 2010 Aug;45(4):276-95
pubmed: 20522000
Cell Rep. 2017 Oct 3;21(1):1-9
pubmed: 28978464
Int J Cardiol. 2013 Oct 9;168(4):3160-72
pubmed: 23932046
Crit Care Med. 2014 May;42(5):e345-54
pubmed: 24448199
Prostaglandins Other Lipid Mediat. 2016 Sep;125:30-9
pubmed: 27179554
J Am Soc Nephrol. 2017 May;28(5):1534-1551
pubmed: 27932476
J Clin Invest. 2012 Mar;122(3):1109-18
pubmed: 22326951
Bio Protoc. 2016 Sep 5;6(17):
pubmed: 28573161
Circ Res. 2018 Mar 2;122(5):712-729
pubmed: 29284690
Am J Physiol Endocrinol Metab. 2012 Sep 1;303(5):E563-75
pubmed: 22739108
Am J Physiol Heart Circ Physiol. 2015 May 1;308(9):H1020-9
pubmed: 25724490
NCHS Data Brief. 2017 Oct;(288):1-8
pubmed: 29155689
J Biol Chem. 2018 Mar 2;293(9):3281-3292
pubmed: 29298899
Autophagy. 2015;11(1):46-59
pubmed: 25484077
Am J Physiol Renal Physiol. 2007 Jul;293(1):F342-9
pubmed: 17442729