Article Text


  1. R V Richardson*,
  2. C J Kenyon,
  3. A J W Thomson,
  4. C M Moran,
  5. G A Gray,
  6. K E Chapman
  1. Centre for Cardiovascular Science, The University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, EH16 4TJ, UK


    Variation in the glucocorticoid receptor (GR) associates with relative glucocorticoid resistance, hypertension and increased cardiovascular disease risk in humans. Mice heterozygous for the glucocorticoid receptor (GR+/−) are similarly glucocorticoid resistant with raised circulating glucocorticoid levels and elevated blood pressure; susceptibility to heart disease is uncharacterised. Here we describe the cardiac phenotype of adult male GR+/− mice and show evidence of impaired cardiac remodelling in response to pharmacological challenge.

    Heart weight (% body weight) is unchanged in 12 week old GR+/− mice (WT:0.57±0.03%, GR+/−:0.61±0.03%), but cardiomyocyte cross-sectional area is reduced (WT:240±21 µm2, GR+/−:193±9.0 µm2, p<0.05), and cardiac nuclei density is increased (nuclei/field; WT:67±1, GR+/−:74±2, p<0.05), suggesting GR+/− mice have more but smaller cardiomyocytes than WT. Whilst histological analysis does not reveal differences in fibrosis, cardiac levels of mRNA encoding connective tissue growth factor are reduced in GR+/− mice (WT:100±12%, GR+/−:65±4%, p<0.05) implying subtle alterations in pro-fibrotic signalling. Echocardiography demonstrates comparable cardiac function in 10 week old GR+/− and WT mice.

    Intriguingly, preliminary data show cardiac hypertrophy in response to angiotensin II infusion (100 ngkg-1 min-1 by osmotic mini-pump) is attenuated in GR+/− mice (heart weight/tibia length Vehicle: WT 7.47±0.326 mg/mm, GR+/−7.29 mg/mm; AngII: WT 8.66±0.249 mg/mm, GR+/−8.07±0.217 mg/mm, p<0.05 (AngII treatment)).

    These data show that GR deficiency alters the size and number of cardiomyocytes and that, whilst adult GR+/− mice match WT cardiac function under basal conditions, cardiac remodelling following pathological challenge is attenuated. Further characterisation of the GR+/− cardiac phenotype may provide critical insights into how GR variation in humans increases risk of heart disease.

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