Abstract 526: Free Fatty Acid Receptor 4 is Required for an Adaptive Response to Pathologic Pressure Overload-induced Heart Failure in Mice

Abstract

Background: Our previous results indicate that eicosapentaenoic acid (EPA) prevents interstitial fibrosis and pathologic remodeling in the transverse aortic constriction (TAC) model of pressure overload induced heart failure in mice. However, EPA supplementation did not lead to incorporation into cardiac myocytes or fibroblasts in vivo , a traditional mechanism of action. Interestingly, we found that free fatty acid receptor 4 (Ffar4), a G-protein coupled receptor for long-chain fatty acids, was expressed in cardiac myocytes and fibroblasts. In primary cultures of cardiac fibroblasts, Ffar4 was sufficient and required to prevent TGFβ1-induced fibrosis, suggesting Ffar4 might mediate EPA cardioprotection. Methods: To understand the function of Ffar4 in the heart in vivo , we examined the response to TAC in male and female Ffar4 knockout mice (Ffar4KO) under basal conditions without EPA supplementation. Results: In male Ffar4KO mice, TAC induced a worsened dilated cardiomyopathy relative to wild-type (WT) mice. Specifically, in male Ffar4KO mice, TAC produced more hypertrophy (Heart weight: WT: 175±8 mg, n=14; Ffar4KO: 223±14 mg, n=10; P <0.05), and generated more severe systolic and diastolic dysfunction (Ejection Fraction: WT: 42±3%, n=14; Ffar4KO: 28±4%, n=10; P <0.05) (E/A ratio: WT: 2.0±0.2, n=12; Ffar4KO: 3.7±0.5, n=9; P <0.05). However, TAC induced similar levels of interstitial fibrosis in male Ffar4 KO and WT mice (WT: 9.6±1.8%, n=14; Ffar4KO: 7.4±1.1%, n=10; ns ). While TAC worsened outcomes in male Ffar4KO mice, TAC in Ffar4 KO female mice produced no significant differences in the degree of hypertrophy or contractile dysfunction relative to WT mice. Discussion: Our results indicate that Ffar4 is required for an adaptive response to pathologic pressure overload in male mice. The lack of an exaggerated fibrotic response was surprising given our previous results indicating that in cardiac fibroblasts, Ffar4 prevents TGFβ1-induced fibrosis. This might indicate that Ffar4 signaling is minimal in fibroblasts under conditions of low omega-3 fatty acid levels. This result also suggests that the worsened contractile dysfunction in Ffar4KO mice is unrelated to fibrosis, but involves a direct effect in cardiac myocytes.