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

• DOI: 10.1038/srep15404
• Publication Date: 2015-10-21T09:02:24Z
• Authors: Lejla Medzikovic; Cees A. Schumacher; Arie O. Verkerk; Elza D. van Deel; Rianne Wolswinkel; Ingeborg van der ...; Natascha Bleeker; Daniella Cakici; Maarten M. G. van...; Farid Meggouh; Esther E. Creemers; Carol Ann Remme; Antonius Baartscheer; Robbert J. de Winter; Carlie J. M. de V...; E. Karin Arkenbout; Vivian de Waard
• Keywords: Heart Failure; Mice, Knockout; 0301 basic medicine; Ventricular Remodeling; Isoproterenol; Adrenergic beta-Agonists; Myocardial Contraction; Article; Mice; 03 medical and health sciences; Nuclear Receptor Subfamily 4, Group A, Member 1; Animals; Homeostasis; Humans; Calcium; Myocytes, Cardiac

AbstractDistinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca2+ ([Ca2+]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 [Ca2+]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 [Ca2+]i, Ca2+-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 Ca2+ homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca2+ homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure.