ABSTRACT Heart disease and heart failure are important causes of morbidity and mortality, affecting approximately 300 million people, at an enormous cost. Although current treatments slow the progression of these diseases, there has been little progress in preventing the compensated heart transitioning to that of a failing one. The Prostaglandin E2 (PGE2) receptor subtypes EP3 and EP4 are most abundant in the heart and activate different signaling pathways (Gαi for EP3, Gαs for EP4). Compelling data from my laboratory shows that EP3 expression is increased in the pathologically diseased heart produced by myocardial infarction (MI) or Angiotensin II- dependent hypertension (Ang II-HTN), that stimulation of the EP3 receptor decreases cardiac contractility whereas EP4 increases it and that overexpression of EP4 in the failing heart improves cardiac function. The failing heart switches from fatty acid (FA) oxidation to reliance on glucose. Coupled with this are alterations in mitochondrial function. Thus, mitochondrial dysfunction is an important player in the pathogenesis of heart failure. Our previous gene array data showed dramatic down regulation of mitochondrial genes in mice in which the EP4 receptor was deleted in cardiomyocytes; allowing PGE2 to act via the EP3 receptor and new data shows that an EP3 agonist reduces Complex I activity and ATP levels in adult mouse cardiomyocytes. mRNAs for proteins that alter both FA oxidation and their transport into mitochondria; specifically, carnitine palmitoyl transferase (CPT) were also down regulated in EP4 KO hearts. In other tissues, CPT activity was reportedly regulated by the transcription factor/orphan receptor NR4A2 (Nurr1) in a PGE2-dependent process but whether this occurs in the heart is unstudied. Since heart failure is characterized by reduced FA oxidation, we propose the novel overall hypothesis: EP3 is increased during cardiac injury and impairs mitochondrial function due to reduced fatty acid import via diminished CPT activity. This is mediated by decreased activity of the transcription factor, NR4A2. Ultimately these events contribute to heart failure. To test this hypothesis, we propose 3 aims that will use a new conditional and cardiomyocyte-specific EP3 KO mouse model coupled with an EP3 overexpressing transgenic mouse to determine whether upregulation of cardiomyocyte EP3 contributes to impaired contractile function and reduced mitochondrial function in heart failure caused by Ang II-HTN and MI. The study also examines whether PGE2 via its EP3 receptor reduces import of fatty acids into mitochondria via decreased activity of the transcription factor NR4A2 which subsequently reduces CPT activity; and whether these events reduce subsequent ATP levels. The proposal employs a multidisciplinary approach including physiological, biochemical and imaging studies that will impact the treatment of heart failure.