Abstract 255: Novel Role for Free Fatty Acid Receptor 4 in Response to Pathologic Pressure Overload-Induced Heart Failure in Mice

Abstract

Free fatty acid receptor 4 (Ffar4, GPR120) is a GPCR for long chain fatty acids, including omega-3 polyunsaturated fatty acids (ω3-PUFAs). Previously, we demonstrated that eicosapentaenoic acid (EPA), an ω3-PUFA, prevents interstitial fibrosis and contractile dysfunction in pressure overload heart failure (transverse aortic constriction, TAC), but EPA was not incorporated into cardiac myocytes or fibroblasts, the traditional mechanism of action. Therefore, we hypothesized that Ffar4 is necessary for the anti-fibrotic and cardioprotective effects of EPA. In fact, we previously found that in primary cardiac fibroblasts, Ffar4 was sufficient and necessary to prevent TGFβ1-induced fibrosis. Here, we were surprised to find that Ffar4 also has important ω3-independent effects in cardiac myocytes in vivo . In mice with systemic deletion of Ffar4 (Ffar4KO mice) on a standard, corn oil diet (no EPA supplementation), TAC induced significantly more cardiac hypertrophy and more systolic (ejection fraction) and diastolic dysfunction (E/A ratio), but without excess fibrosis after 4 weeks. Mechanistically, transcriptome analysis in cardiac myocytes 3 days post-TAC indicated a deficiency of transcription in Ffar4KO myocytes. Sorting based on gene ontology indicated that genes functionally categorized as cell death and inflammation, including ilrn1 , hmox1 , Il33 , and ptgs2 (cox2) were not induced in the Ffar4KO myocytes. Ffar4 also activates cytoplasmic phospholipase A2 (cPLA2) inducing the production of oxylipins, and systemic deletion of cPLA2 induces exaggerated hypertrophy during development and following TAC. TAC increased cPLA2 expression in WT, but not Ffar4KO cardiac myocytes and oxylipin production was reduced in Ffar4KO mice. Finally, we confirmed that Ffar4 is expressed in human heart and down-regulated in heart failure. In summary, our data identify a novel, ω3-independent cardioprotective role for Ffar4 in cardiac myocytes.