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The Nuclear Receptor NR4A2 Coordinates Transcriptional Remodeling of Metabolic, Calcium, and Growth Signaling Networks in Adult Rat Ventricular Myocytes
Author(s) -
Ashraf Sadia,
Harmancey Romain
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.848.7
Subject(s) - myocyte , heart failure , nuclear receptor , muscle hypertrophy , gata4 , microbiology and biotechnology , transcription factor , stimulation , biology , medicine , signal transduction , endocrinology , receptor , gene , biochemistry
Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and contractile dysfunction in heart failure. Better understanding of β‐adrenergic signaling regulation in cardiomyocytes should provide therapeutic insights for heart failure management. The orphan nuclear receptor NR4A2 is an immediate early response gene activated in the heart under various stress conditions. The goal of this study was to identify the transcriptional networks regulated by NR4A2 in cardiomyocytes and their effect on cellular remodeling induced by sustained β‐adrenergic stimulation. Isoproterenol (ISO; 10 μM) induced a transient increase in NR4A2 mRNA levels in H9c2 cardiomyoblasts (5‐fold) and in isolated adult rat ventricular cardiomyocytes (ARVM; 80‐fold) that peaked after 1 hour before returning to baseline levels within 24 hours of stimulation. In addition, ISO induced rapid and transient nuclear localization of NR4A2 as visualized by immunofluorescence. Total RNA sequencing revealed that adenovirus‐mediated overexpression of NR4A2 in ARVM led to the regulation of genes associated with cAMP signaling, cell growth and proliferation, glucose metabolism, and calcium homeostasis. These transcriptional events were accompanied by the down‐regulation of genes encoding pro‐hypertrophic transcription factors implicated in pathological remodeling of the stressed heart (Nfatc2, Nfatc3, Gata4, Gata6, and Stat5a). In ARVM chronically treated with ISO for 48 hours, NR4A2 overexpression prevented both the up‐regulation of the pathologic hypertrophic marker BNP and an overall increase in protein synthesis rates as determined by measurement of [ 3 H]leucine incorporation. The overexpression of NR4A2 also prevented ISO‐induced increase in cell surface area for both ARVM and H9c2 cardiomyoblasts. In conclusion, the results expose NR4A2 as a potential regulator of cardiomyocyte metabolic and functional remodeling under stress conditions. NR4A2 may promote antihypertrophic pathways to counteract the detrimental effects of excessive sympathetic system activity. Support or Funding Information Supported by grants R00 HL112952, P01 HL051971, and P20 GM104357 from the National Institutes of Health This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .