Projects per year
Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention has 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 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.
|Journal||Journal of Endocrinology|
|Early online date||9 Jan 2017|
|Publication status||Published - Mar 2017|
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- 1 Finished
GLUCOCORTICOID RECEPTOR IN THE EARLY LIFE PROGRAMMING OF CARDIAC RESILIANCE
Chapman, K., Denvir, M., Gray, G. & Holmes, M.
1/12/16 → 30/11/19
- Centre for Cardiovascular Science
- Deanery of Clinical Sciences - UoE Retired Staff
Person: Academic: Research Active , Affiliated Independent Researcher