title: EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4.
abstract: 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 EPA- and 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 protein-coupled 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.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Eclov
authors.affiliation: Cardiovascular Research, Sanford Research, Sioux Falls, SD.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Qian
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, PA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Redetzke
authors.affiliation: Cardiovascular Research, Sanford Research, Sioux Falls, SD.
authors.forename: Quanhai
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN.
authors.forename: Chastity L
authors.initials: CL
authors.lastname: Healy
authors.affiliation: Cardiovascular Research, Sanford Research, Sioux Falls, SD.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Ortmeier
authors.affiliation: Cardiovascular Research, Sanford Research, Sioux Falls, SD.
authors.forename: Erin
authors.initials: E
authors.lastname: Harmon
authors.affiliation: Department of Nutritional Sciences, Pennsylvania State University, University Park, PA tdoconne@umn.edu gcs13@psu.edu.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Shearer
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN tdoconne@umn.edu gcs13@psu.edu.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Connell
mesh_terms: D000818:Animals; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000627:therapeutic use*; D015118:Eicosapentaenoic Acid / Q000627:therapeutic use*; D005230:Fatty Acids, Nonesterified / Q000627:therapeutic use*; D005355:Fibrosis / Q000517:prevention & control*; D006333:Heart Failure / Q000517:prevention & control*; D051379:Mice; D011897:Random Allocation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C498007:FFAR4 protein, mouse; D005230:Fatty Acids, Nonesterified; D043562:Receptors, G-Protein-Coupled; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid
keywords: docosahexaenoic acid; eicosapentaenoic acid; fibroblast; omega-3 polyunsaturated fatty acids; transverse aortic constriction