title: Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis.
abstract: Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types.
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Richardson
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Batchen
authors.affiliation: Edinburgh Preclinical ImagingUniversity of Edinburgh, Edinburgh, UK.
authors.forename: Adrian J W
authors.initials: AJ
authors.lastname: Thomson
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Rowan
authors.initials: R
authors.lastname: Darroch
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Xinlu
authors.initials: X
authors.lastname: Pan
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Eva A
authors.initials: EA
authors.lastname: Rog-Zielinska
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Wiktoria
authors.initials: W
authors.lastname: Wyrzykowska
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scullion
authors.affiliation: DieteticsNutrition, and Biological Sciences Department, Queen Margaret University, Musselburgh, UK.
authors.forename: Emad A S
authors.initials: EA
authors.lastname: Al-Dujaili
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Diaz
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.|Edinburgh Preclinical ImagingUniversity of Edinburgh, Edinburgh, UK.
authors.forename: Carmel M
authors.initials: CM
authors.lastname: Moran
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Gray
authors.affiliation: University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK Karen.Chapman@ed.ac.uk.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000097:blood; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013148:Spironolactone / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000235:genetics
chemical_list: D011965:Receptors, Glucocorticoid; D013148:Spironolactone; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains; D003345:Corticosterone
keywords: fibrosis; glucocorticoid receptor; heart; isovolumetric contraction; mineralocorticoid receptor