EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: Potential role of free fatty acid receptor 4

Julie A. Eclov, Qingwen Qian, Rebecca Redetzke, Quanhai Chen, Steven C. Wu, Chastity L. Healy, Steven B. Ortmeier, Erin Harmon, Gregory C. Shearer, Timothy D. O'Connell

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


Heart failure with preserved ejection fraction (HFpEF) is half of all HF, but standard HF therapies are ineffective. Diastolic dysfunction, often secondary to interstitial fibrosis, is common in HFpEF. Previously, we found that supra-physiologic levels of ω3-PUFAs produced by 12 weeks of ω3-dietary supplementation prevented fibrosis and contractile dysfunction following pressure overload [transverse aortic constriction (TAC)], a model that resembles aspects of remodeling in HFpEF. This raised several questions regarding ω3-concentration-dependent cardioprotection, the specific role of EPA and DHA, and the relationship between prevention of fibrosis and contractile dysfunction. To achieve more clinically relevant ω3-levels and test individual ω3-PUFAs, we shortened the ω3-diet regimen and used EPAand DHA-specific diets to examine remodeling following TAC. The shorter diet regimen produced ω3-PUFA levels closer to Western clinics. Further, EPA, but not DHA, prevented fibrosis following TAC. However, neither ω3-PUFA prevented contractile dysfunction, perhaps due to reduced uptake of ω3-PUFA. Interestingly, EPA did not accumulate in cardiac fibroblasts. However, FFA receptor 4, a G proteincoupled receptor for ω3-PUFAs, was sufficient and required to block transforming growth factor β1-fibrotic signaling in cultured cardiac fibroblasts, suggesting a novel mechanism for EPA. In summary, EPA-mediated prevention of fibrosis could represent a novel therapy for HFpEF.

Original languageEnglish (US)
Pages (from-to)2297-2308
Number of pages12
JournalJournal of lipid research
Issue number12
StatePublished - Dec 1 2015

Bibliographical note

Publisher Copyright:
© 2015 by the American Society for Biochemistry and Molecular Biology, Inc.


  • Docosahexaenoic acid
  • Eicosapentaenoic acid
  • Fibroblast
  • Omega-3 polyunsaturated fatty acids
  • Transverse aortic constriction


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