Ffar4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex clinicalsyndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, non-resolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (FFAR4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that FFAR4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of FFAR4 (FFAR4KO) were fed a high-fat/high-sucrose diet with LNAME in their water to induce HFpEF-MetS. In male FFAR4KO mice, this HFpEFMetS diet induced similar metabolic deficits, but worsened diastolic function and microvascular rarefaction relative to wild-type (WT) mice. Conversely, in female FFAR4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In FFAR4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachadonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18- HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male FFAR4KO mice, and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that FFAR4 controls the proinflammatory/pro-resolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.