Variation in the human glucocorticoid receptor (GR) gene associates with relative glucocorticoid resistance, hypertension and increased cardiovascular disease risk. Mice heterozygous for a null GR mutation (GR+/−) are also glucocorticoid resistant with raised circulating glucocorticoid levels and elevated blood pressure in adulthood. We have characterised the cardiac phenotype of these mice throughout development and investigated their response to cardiovascular challenge in adulthood.
GR+/− mice are present at half the expected number at weaning (3 weeks old). Cardiac function is impaired in GR+/− mice at embryonic day (E) 17.5, with Doppler measurements (Visualsonics Vevo770 ultrasound) of blood flow within the left ventricle showing a detrimental increase in the myocardial performance index (representing combined systolic and diastolic function), due to prolonged isovolumetric contraction and relaxation times. This is normalised by postnatal day 7 and remains comparable to WT littermates in adult male GR+/− mice. At E17.5, GR+/− mice lack the normal maturational increase in cardiac mRNA encoding myosin heavy chain α (MHCα) and atrial-natriuretic peptide (ANP). By adulthood, MHCα mRNA levels were equivalent to WT, whilst ANP remained lower (P<0.05). Furthermore, cardiomyocyte cross-sectional area was reduced in adult GR+/− mice compared with WT littermates (P<0.05) suggesting a potential underlying vulnerability to cardiac challenge. Cardiac remodelling was investigated in adult male mice. Angiotensin II infusion (200 ng/kg per min, 14 days) caused similar increases in heart weight (P<0.0001), cardiomyocyte hypertrophy (P<0.001) and collagen deposition (P<0.0001) in WT and GR+/− mice, indicating that GR haploinsufficiency does not alter pathological cardiac remodelling in this model.
In summary, reduced GR density alters the trajectory of cardiac maturation during development. Whilst compensatory adaptations occur in surviving mice for the functional impairment seen in utero, subtle structural and molecular abnormalities remain in adulthood and are likely to contribute to cardiovascular disease risk, in combination with the elevated blood pressure and glucocorticoid levels.