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

• Published in: Scientific reports 2015-10, Vol.5 (1), p.15404-15404, Article 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: Article
• Language: English
• 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
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep15404

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.