Document text
Principal Investigator: Timothy D O'Connell
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $665,482
Funding agency: National Heart Lung and Blood Institute
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 cohorts. Although more patients survive MI, post-MI HF is rising. Here, we
propose Ffar4 as 1) a novel cardioprotective, fatty acid nutrient sensor, 2) a potential therapeutic target to
attenuate post-MI remodeling, and 3) the mechanistic basis for EPA cardioprotection.
Terms: <21+ years old><Acute myocardial infarct><Acute myocardial infarction><Adult><Adult Human><Affect><Agonist><Antiinflammatory Effect><Attenuated><Autoregulation><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cardiovascular Diseases><Cell Communication and Signaling><Cell Death><Cell Signaling><Chemotactic Cytokines><Chemotaxis><Clinical><Coronary Disease><Coronary heart disease><Data><Dependence><Diet><Disease Outcome><Dose><Dysfunction><EC 3.1.1.4><Eicosapentaenoic Acid><Fatty Acids><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Free Fatty Acids><Functional disorder><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Genes><Genetic Polymorphism><Heart><Heart Injuries><Heart Muscle Cells><Heart failure><Heart myocyte><Homeostasis><Homologous Chemotactic Cytokines><Human><Hypoxia><Hypoxic><Immune infiltrates><Immune response><Immunological response><In Vitro><Incidence><Infarction><Inflammatory><Intercrines><Intracellular Communication and Signaling><Ischemia><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Lecithinase A2><Macrophage><Measures><Mediating><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Muscle Cells><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocytes><Mφ><Nonesterified Fatty Acids><Nutrient><Omega-3 Fatty Acids><Omega-3 PUFA><Omega-3 Polyunsaturated Fatty Acid><Omega3><Outcome><Oxygen Deficiency><PLA2><Pathologic><Patients><Phospholipase A2><Physiological Homeostasis><Physiopathology><Polyunsaturated Fatty Acids><Production><Receptor Protein><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Reporting><Role><SIS cytokines><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Single Base Polymorphism><Single Nucleotide Polymorphism><Supplementation><Testing><Therapeutic><Thesaurismosis><Timnodonic Acid><Wild Type Mouse><adulthood><anti-inflammatory effect><aorta constriction><atherosclerotic heart disease><attenuate><attenuates><biological signal transduction><cardiac failure><cardiac fibrosis><cardiac infarct><cardiac injury><cardiac ischemia><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disorder><chemoattractant cytokine><chemokine><cohort><coronary attack><coronary disorder><coronary fibrosis><coronary infarct><coronary infarction><coronary ischemia><cytokine><diets><eicosapentanoic acid><experiment><experimental research><experimental study><experiments><fibrotic heart><heart attack><heart fibrosis><heart infarct><heart infarction><heart ischemia><host response><immune cell infiltrate><immune system response><immunoresponse><improved><improved outcome><infarct><interstitial><ischemia injury><ischemic injury><lecithinase A><long chain fatty acid><metabolism disorder><mortality><myocardial fibrosis><myocardial ischemia/hypoxia><myocardium ischemia><n-3 Fatty Acids><necrocytosis><novel><offspring><omega-3><pathophysiology><percutaneous coronary intervention><phosphatidase><phosphatidolipase><phosphatidylcholine 2 acylhydrolase><polymorphism><pressure><prevent><preventing><receptor><receptor function><recruit><reperfusion><sensor><single nucleotide variant><social role><therapeutic target><wildtype mouse><ω-3 fatty acids>