Abstract 323: Metabolic Transformation of Fatty Acids Defines Resolving Versus Non-Resolving Inflammation in Obesity-Associated Heart Failure

Abstract

Whether and how fat intake contributes to persistent inflammation in obesity is unclear. Here, we report the differential metabolic transformation of fatty acids in heart failure (HF) pathology in the setting of obesity. We used permanent coronary ligation to induce myocardial infarction (MI) leading to acute (d1), healing phase (d5) and subsequent chronic HF phase (d28) in male C57BL/6J mice, while maintaining naïve controls at day (d)0. Prior to MI, 100 two month-old mice were subjected to n-6 fatty acids (safflower oil; SO; 22Kcal) for 3 months, with subsequent randomized allocation of 50 mice to docosahexaenoic acid (DHA; 22Kcal) enriched n-3 fatty acids for the next 2 months, while maintaining SO control in the remaining 50 mice. Both groups gained significant weight and fat mass independent of lean mass confirmed by magnetic resonance imaging. Post-MI survival and left ventricular (LV) function was decreased in SO-fed mice with downregulation of multiple inflammation resolution mechanisms in the spleen, infarcted LV, and kidney. DHA increased Ly6C low macrophages, MRC, Arg-1, YM1 and FFAR4 (GPR120) during the acute and resolving phase from d1 to d5 post-MI as compared with SO-fed mice. DHA-improved post-MI survival at d28, together with increased levels of D-series resolvins (RvD1, RvD2, RvD4, RvD5), maresin 1, and RvE3, and lower levels of prostaglandins (PGD 2 , PGE 2 , PGF2 α ), leukotriene B 4 (LTB 4 ), 20-OH-LTB 4 , thromboxane B2 and lipoxin A 4 in the resolving phase. During chronic HF at d28 post-MI, DHA increased CD4 + /CD127 - with increased expression of FOXp3 in the LV. DHA reduced FFAR1-3 , neprilysin activity and simultaneously increased FFAR4 in the kidney as compared with SO post-MI. In contrast, SO-induced overactivation of pro-inflammatory FFAR1 (GPR40) and reduction of anti-inflammatory FFAR4 tracked with increased serum creatinine and IL-1β, and decreased ALX/ FPR2 in kidney at d28 post-MI. Overall, DHA intake modulates the splenocardiac resolving phase with generation of proresolving mediators, augmentation of Ly6C low macrophages, and suppression of prostaglandins post-MI. Thus, the metabolic transformation of n-3 and -6 fatty acids can regulate resolution versus non-resolution of inflammation in HF post-MI in the setting of obesity.