Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.
18-hydroxyeicosapentaenoic acid (18-HEPE)
Cytoplasmic phospholipase A2α (cPLA2α)
Eicosapentaenoic acid (EPA)
Free fatty acid receptor 4 (Ffar4)
GPR120
Heart failure
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
16 03 2022
16 03 2022
Historique:
received:
23
11
2020
accepted:
19
03
2021
pubmed:
23
3
2021
medline:
26
4
2022
entrez:
22
3
2021
Statut:
ppublish
Résumé
Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.
Identifiants
pubmed: 33752243
pii: 6180073
doi: 10.1093/cvr/cvab111
pmc: PMC8930069
doi:
Substances chimiques
Fatty Acids
0
Fatty Acids, Nonesterified
0
Oxylipins
0
Receptors, G-Protein-Coupled
0
Eicosapentaenoic Acid
AAN7QOV9EA
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
1061-1073Subventions
Organisme : NHGRI NIH HHS
ID : R15 HG006915
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL140074
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL152215
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130099
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL140067
Pays : United States
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
Références
Diabetologia. 2014 Jun;57(6):1182-91
pubmed: 24663807
Mol Pharmacol. 2013 Nov;84(5):710-25
pubmed: 23979972
Circulation. 2011 Feb 15;123(6):584-93
pubmed: 21282499
J Exp Med. 2009 Jul 6;206(7):1565-74
pubmed: 19546247
J Lipid Res. 2015 Dec;56(12):2297-308
pubmed: 26435012
Prostaglandins Leukot Essent Fatty Acids. 2018 Oct;137:26-38
pubmed: 30293594
Dis Markers. 2019 Oct 27;2019:5058313
pubmed: 31772688
Biochem Biophys Res Commun. 2007 Mar 9;354(2):591-7
pubmed: 17250804
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1524-30
pubmed: 16627800
Circulation. 2017 Apr 11;135(15):e867-e884
pubmed: 28289069
EMBO Mol Med. 2018 Mar;10(3):
pubmed: 29343498
Br J Nutr. 2015 Jun 14;113(11):1677-88
pubmed: 25916176
Prostaglandins Leukot Essent Fatty Acids. 2008 Dec;79(6):215-22
pubmed: 19042114
Br J Pharmacol. 2019 Apr;176(8):1038-1050
pubmed: 29468666
Biochem Pharmacol. 2016 Aug 15;114:3-13
pubmed: 27002183
J Exp Med. 2005 Mar 7;201(5):713-22
pubmed: 15753205
PLoS One. 2014 Nov 13;9(11):e111471
pubmed: 25393536
Nat Med. 2003 Jul;9(7):944-51
pubmed: 12808451
Arterioscler Thromb Vasc Biol. 2019 Dec;39(12):2457-2467
pubmed: 31597448
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):515-22
pubmed: 18320172
Diabetes Obes Metab. 2014 Nov;16(11):1128-39
pubmed: 24919766
Immunology. 2014 Sep;143(1):81-95
pubmed: 24673159
Endocr J. 2017 Nov 29;64(11):1055-1061
pubmed: 28824022
Nature. 2012 Feb 19;483(7389):350-4
pubmed: 22343897
J Biol Chem. 2014 May 30;289(22):15751-63
pubmed: 24742677
J Exp Med. 2014 Jul 28;211(8):1673-87
pubmed: 25049337
Arch Toxicol. 2016 Feb;90(2):359-73
pubmed: 25600587
Nat Commun. 2016 Nov 17;7:13479
pubmed: 27853148
Br J Pharmacol. 2018 Apr;175(8):1205-1216
pubmed: 28925017
J Nutr Biochem. 2013 Jan;24(1):204-12
pubmed: 22901690
Mol Pharmacol. 2012 May;81(5):631-42
pubmed: 22282525
J Lipid Res. 2015 Aug;56(8):1386-402
pubmed: 25838312
Biochem J. 1996 Sep 15;318 ( Pt 3):797-803
pubmed: 8836122
Am J Physiol Heart Circ Physiol. 2010 Jul;299(1):H153-64
pubmed: 20435846
Circulation. 2018 Mar 20;137(12):e67-e492
pubmed: 29386200
Circ Res. 2009 Jan 30;104(2):265-75, 11p following 275
pubmed: 19074476
Mol Cell Biochem. 2017 May;429(1-2):151-165
pubmed: 28251434
J Am Coll Cardiol. 2010 Mar 16;55(11):1057-65
pubmed: 20223363
Circ Res. 2016 Jun 10;118(12):1940-1959
pubmed: 27283533
Nat Med. 2005 Jan;11(1):90-4
pubmed: 15619630
Br J Pharmacol. 2019 Apr;176(8):1024-1037
pubmed: 29679485
Front Pharmacol. 2014 Nov 06;5:236
pubmed: 25414667
JACC Basic Transl Sci. 2020 Mar 04;5(3):282-295
pubmed: 32215350
Cell. 2010 Sep 3;142(5):687-98
pubmed: 20813258