Endocrine Abstracts

Variation in the glucocorticoid receptor (GR) gene associates with relative glucocorticoid resistance, hypertension and increased cardiovascular disease risk in humans. To investigate the contribution of cardiac GR to this phenotype we have characterised adult male mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO) and have found left ventricular function to be impaired.

SMGRKO mice, generated by crossing GR ‘floxed’ mice (congenic on C57BL/6J) with SM22α-Cre mice, have reduced cardiac GR protein and mRNA levels (by 52 and 57%, respectively), compared to Cre-negative littermate controls.

The Visualsonics Vevo 770 High-Resolution Ultrasound In Vivo Micro-Imaging System was used to assess cardiac function at 10 weeks of age. Mitral valve Doppler showed a detrimental increase in the myocardial performance index (MPI), a marker of combined systolic and diastolic function, in SMGRKO mice. This was primarily due to greater isovolumetric contraction time (control: 12.9±0.8 ms, SMGRKO: 15.5±0.6, P<0.05) indicating impairment of the initial left ventricular contractile phase.

Heart weight (% body weight) is increased in SMGRKO mice (control: 0.5±0.02%, SMGRKO: 0.55±0.01%, P<0.05) and they have elevated levels of cardiac mRNA encoding myosin heavy chain-β (control: 100±9%, SMGRKO: 151±16%, P<0.05), mineralocorticoid receptor (MR (control: 100±14%, SMGRKO: 151±19%, P<0.05)) and pro-fibrotic factors (collagen, TGFβ?, CTGF). Cardiac expression of Ca²⁺ handling genes was unaltered. Histopathology shows fibrosis and a trend for increased cardiomyocyte cross sectional area in the left ventricle of SMGRKO mice, suggestive of cardiomyocyte hypertrophy and pathological remodelling despite normal blood pressure.

These data demonstrate that cardiomyocyte/smooth muscle GR deficiency causes pathological changes in the left ventricle resulting in impairment of isovolumetric contraction in 10 week old mice. The findings support a role for cardiomyocyte GR in determination of cardiovascular disease risk.

Declaration of funding

R.V. Richardson is supported by an MRC PhD Studentship.