title: Development of dilated cardiomyopathy and impaired calcium homeostasis with cardiac-specific deletion of ESRRβ.
abstract: Mechanisms underlying the development of idiopathic dilated cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor-β (ESRRβ), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRβ (MHC-ERRB KO) develop DCM and sudden death at ~10 mo of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRβ protein is absent from the nucleus of cardiomyocytes from patients with DCM but not other forms of cardiomyopathy (ischemic, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRβ is a critical component in the onset of DCM by affecting contractility and calcium balance.NEW & NOTEWORTHYEstrogen-related receptor-β (ESRRβ) is highly expressed in the heart and cardiac-specific deletion results in the development of a dilated cardiomyopathy (DCM). ESRRβ is mislocalized in human myocardium samples with DCM, suggesting a possible role for ESRRβ in the pathogenesis of DCM in humans.
authors.affiliation: Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts; gcrowe@uab.edu.|Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Glenn C
authors.identifier: http://orcid.org/0000-0002-8195-9605
authors.initials: GC
authors.lastname: Rowe
authors.affiliation: Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.affiliation: Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Evan L
authors.initials: EL
authors.lastname: Graham
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Martin
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.|Division of Cardiology, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.affiliation: Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Saffitz
authors.affiliation: Cardiovascular Institute, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts.|Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Arany
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology*; D016757:Death, Sudden, Cardiac; D003576:Electron Transport Complex IV / Q000235:genetics; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054792:Muscle, Striated / Q000378:metabolism; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics*
chemical_list: C490918:ESRRB protein, human; C098925:Esrrb protein, mouse; D011960:Receptors, Estrogen; D003576:Electron Transport Complex IV; D002118:Calcium
keywords: calcium handling; dilated cardiomyopathy; estrogen-related receptor