Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload

Katie Murphy, Brian A. Harsch, Chastity L Healy, Sonal S. Joshi, Shue Huang, Rachel E. Walker, Brandon M Wagner, Katherine M. Ernste, Wei Huang, Robert C. Block, Casey D. Wright, Nathan Tintle, Brian C. Jensen, Quinn S. Wells, Gregory C. Shearer, Timothy D. O'Connell

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Aims: 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. Methods and results: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1061-1073
Number of pages13
JournalCardiovascular Research
Volume118
Issue number4
DOIs
StatePublished - Mar 1 2022

Bibliographical note

Publisher Copyright:
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected].

Keywords

  • 18-hydroxyeicosapentaenoic acid (18-HEPE)
  • Cytoplasmic phospholipase Aα (cPLAα)
  • Eicosapentaenoic acid (EPA)
  • Free fatty acid receptor 4 (Ffar4)
  • GPR120
  • Heart failure

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