Coronary heart disease (CHD), leading to myocardial infarction (MI) and post-MI heart failure (HF), is a major cause of morbidity and mortality in the US. w3-polyunsaturated fatty acids, like eicosapentaenoic acid (EPA), improve outcomes in CHD and HF, but this is controversial. First, several trials with low-dose w3s have failed, but recent trials with high-dose w3s (REDUCE-IT, OMEGA-REMODEL) report improved outcomes. Second, the mechanism of w3-cardioprotection is unclear, but free fatty acid receptor 4 (Ffar4), a GPCR for long-chain fatty acids, is a novel mechanism to explain w3-cardioprotection. In mice, we were the first to establish that EPA prevents cardiac fibrosis and contractile dysfunction in pressure overload. Yet, EPA was not incorporated into cardiac myocytes or fibroblasts, the traditional mechanism for EPA cardioprotection. Alternatively, we found that Ffar4 is expressed in the heart, and Ffar4 in cardiac fibroblasts in vitro was sufficient and necessary to prevent TGFb1-induced fibrosis. Thus, we hypothesized that EPA-Ffar4 signaling is necessary for EPA cardioprotection. However, we were surprised to find that Ffar4 also has w3-independent effects. In mice with systemic deletion of Ffar4 (Ffar4KO) on a standard diet, we found that TAC worsens remodeling, but without exaggerated fibrosis, highlighting the role of Ffar4 in cardiac myocytes. In myocytes, we found that Ffar4 was necessary for the expression of cardioprotective inflammatory genes and activation of phospholipase A2 (PLA2). In humans, we found that Ffar4 expression is decreased in human HF, and Ffar4 polymorphisms are associated with contractile dysfunction in Framingham Offspring. Here, we propose a novel paradigm where fatty acids function as signaling molecules to maintain cardiac homeostasis. We hypothesize that in cardiac myocytes, Ffar4 functions as an w3-independent cardioprotective, fatty acid nutrient sensor, and that Ffar4 is necessary for EPA cardioprotection. We propose four aims. 1) To determine if cardiac myocyte Ffar4 is necessary to protect against ischemia, cardiac myocyte-specific Ffar4KO mice (CM-Ffar4KO) will be subjected to ischemia-reperfusion (I/R) injury, and we hypothesize worse outcomes in the CM-Ffar4KO. 2) To define cardioprotective Ffar4 signaling mechanisms, following I/R injury in CM-Ffar4KO mice and in hypoxia in cultured myocytes, we will measure cell death, inflammatory cytokines, PLA2-induced oxylipins, and how this affects macrophage recruitment. 3) To determine if Ffar4 is necessary for EPA cardioprotection, CM-Ffar4KO on an EPA-diet will be subjected to I/R injury, and we hypothesize EPA will fail to attenuate remodeling in the CM-Ffar4KO. 4) To determine the therapeutic potential of Ffar4, wild-type mice subjected to I/R injury will treated with the Ffar4 agonist TUG-891 post-MI. In humans, we will test for associations between Ffar4 polymorphisms and CVD in clinical coh...