Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling

Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca 2+ ([Ca 2+ ] i ). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear recepto...

Full description

Saved in:

Bibliographic Details
Published in:	Scientific reports Vol. 5; no. 1; p. 15404
Main Authors:	Medzikovic, Lejla, Schumacher, Cees A., Verkerk, Arie O., van Deel, Elza D., Wolswinkel, Rianne, van der Made, Ingeborg, Bleeker, Natascha, Cakici, Daniella, van den Hoogenhof, Maarten M. G., Meggouh, Farid, Creemers, Esther E., Remme, Carol Ann, Baartscheer, Antonius, de Winter, Robbert J., de Vries, Carlie J. M., Arkenbout, E. Karin, de Waard, Vivian
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 21-10-2015 Nature Publishing Group
Subjects:	13 14/34 14/63 38/71 38/77 631/337/572/2102 64/60 692/308/1426 692/699/75/230 9/74 Adrenergic beta-Agonists - administration & dosage Animals Aorta Calcineurin Calcium (intracellular) Calcium - metabolism Calcium homeostasis Cardiomyocytes Fibrosis Heart diseases Heart failure Heart Failure - genetics Heart Failure - physiopathology Homeostasis Humanities and Social Sciences Humans Isoproterenol Isoproterenol - administration & dosage Mice Mice, Knockout multidisciplinary Muscle contraction Myocardial Contraction - drug effects Myocardial Contraction - genetics Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism Nur77 protein Rodents Science Ventricle Ventricular Remodeling - genetics Ventricular Remodeling - physiology
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca 2+ ([Ca 2+ ] i ). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca 2+ ] i and prolonged action potentials compared to wild type (WT). In vivo , these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes and more cardiac fibrosis in Nur77-KO mice upon chronic isoproterenol stimulation. In line with the observed elevated [Ca 2+ ] i , Ca 2+ -activated phosphatase calcineurin was more active in Nur77-KO mice compared to WT. In contrast, after cardiac pressure overload by aortic constriction, Nur77-KO mice exhibited attenuated remodelling compared to WT. Concluding, Nur77-deficiency results in significantly altered cardiac Ca 2+ homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca 2+ homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/srep15404