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 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.
Department of Medical Biochemistry, University of Amsterdam, The Netherlands.|Department of Cardiology, University of Amsterdam, The Netherlands.
Lejla
L
Medzikovic
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Cees A
CA
Schumacher
Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, The Netherlands.
Arie O
AO
Verkerk
Division of Cardiology, Thoraxcenter, Erasmus Medical Center, University of Rotterdam, The Netherlands.
Elza D
ED
van Deel
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Rianne
R
Wolswinkel
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Ingeborg
I
van der Made
Department of Medical Biochemistry, University of Amsterdam, The Netherlands.
Natascha
N
Bleeker
Department of Medical Biochemistry, University of Amsterdam, The Netherlands.
Daniella
D
Cakici
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Maarten M G
MM
van den Hoogenhof
Department of Medical Biochemistry, University of Amsterdam, The Netherlands.
Farid
F
Meggouh
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Esther E
EE
Creemers
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Carol Ann
CA
Remme
Department of Clinical and Experimental Cardiology, University of Amsterdam, The Netherlands.
Antonius
A
Baartscheer
Department of Cardiology, University of Amsterdam, The Netherlands.
Robbert J
RJ
de Winter
Department of Medical Biochemistry, University of Amsterdam, The Netherlands.
Carlie J M
CJ
de Vries
Department of Cardiology, University of Amsterdam, The Netherlands.|Department of Cardiology, Tergooi Hospital, Blaricum, The Netherlands.
E Karin
EK
Arkenbout
Department of Medical Biochemistry, University of Amsterdam, The Netherlands.
Vivian
V
de Waard
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology
D000318:Adrenergic beta-Agonists; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D007545:Isoproterenol; D002118:Calcium