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Lookup NU author(s): Dr Rachel Richardson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 Society for Endocrinology Printed in Great Britain. 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-B 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.
Author(s): Richardson RV, Batchen EJ, Thomson AJW, Darroch R, Pan X, Rog-Zielinska EA, Wyrzykowska W, Scullion K, Al-Dujaili EAS, Diaz ME, Moran CM, Kenyon CJ, Gray GA, Chapman KE
Publication type: Article
Publication status: Published
Journal: Journal of Endocrinology
Year: 2017
Volume: 232
Issue: 3
Pages: 437-450
Print publication date: 01/03/2017
Online publication date: 05/01/2017
Acceptance date: 05/01/2017
Date deposited: 24/04/2017
ISSN (print): 0022-0795
ISSN (electronic): 1479-6805
Publisher: BioScientifica Ltd.
URL: https://doi.org/10.1530/JOE-16-0458
DOI: 10.1530/JOE-16-0458
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