Abstract 12289: The Nuclear Receptor NR4A1 Regulates Transcriptional Programs Involved in Cardiac Fuel Metabolism and Hypertrophic Growth

Abstract

The transcriptional coregulators, peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) alpha and beta, are inducible master regulators of mitochondrial biogenesis and metabolism. Studies in rodents and in humans have shown that expression and activity of PGC-1 coactivators is downregulated in the failing heart. Surprisingly, we found that adult mice with cardiac-specific deletion of the PGC-1alpha/beta genes exhibit relatively normal cardiac function despite a significant reduction in mitochondrial state 3 respiration, suggesting the existence of a compensatory energy metabolic pathway. Unbiased transcriptional profiling demonstrated upregulation of the orphan nuclear receptor NR4A1 (Nur77) and the related nuclear receptor NR4A3 (Nor1) in PGC-1 null hearts, consistent with an adaptive response to energetic stress. We found that expression of NR4A1 family members is induced in heart by a variety of physiological stress stimuli. In addition, activation of beta-adrenergic signaling with isoproterenol led to rapid and dramatic induction in the expression of all NR4A members in the mouse heart. To identify cardiac NR4A1 targets, total RNA-seq was performed in neonatal rat ventricular myocytes (NRVMs) overexpressing NR4A1. NR4A1 expression of genes involved in glucose uptake/utilization pathways and high energy phosphate transfer including Slc2a4 (Glut4), Eno3 (enolase 3), and Ckmt2 (mitochondrial creatinine kinase). Consistent with the transcriptomic changes, NR4A1 increased myocyte 2-deoxylglucose uptake and oxygen consumption rates (OCR) in these cells. Interestingly, the RNA-seq data also revealed that NR4A1 overexpression downregulated many cardiac pathologic hypertrophic markers such as ANF and BNP. NR4A1 overexpression also significantly inhibited phenylephrine-induced NRVM hypertrophy. Finally, NR4A1 knockout mice exhibit exuberant cardiac hypertrophy following chronic isoproterenol administration. Taken together, these data suggest NR4A1 serves as a stress-induced transcription factor that regulates fuel metabolism and cardiac remodeling. The long-term goal of this project is to determine if activation of this pathway holds therapeutic benefit in acute heart failure.