Specific variations in the human glucocorticoid receptor (GR) gene associate with increased cardiovascular disease risk. GR signalling is essential for cardiac maturation in utero and adult mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice) have cardiac hypertrophy, fibrosis and impaired function. Intriguingly, levels of left ventricle (LV) mRNA encoding the mineralocorticoid receptor (MR), which is pro-fibrotic in heart, rise postnatally in SMGRKO mice in parallel with the development of cardiac fibrosis. Here, the benefit of MR antagonism in limiting cardiac fibrosis was assessed in SMGRKO mice.
SMGRKO mice (generated via SM22α-Cre mediated deletion of GR) and control (Cre−) littermates were treated from birth with vehicle or 20 mg/kg per day spironolactone, an MR antagonist, administered in the drinking water to lactating dams until weaning then to offspring (n=1013/group). At 8 weeks of age, hearts were collected for histology and mRNA profiling. Data were analysed by two-way ANOVA with Tukeys multiple comparisons test.
Heart weight in male SMGRKO mice was higher than controls irrespective of spironolactone treatment (P<0.01). Interestingly, spironolactone modestly reduced heart weight in both genotypes (P<0.05).
PicroSirius Red staining showed greater collagen levels in LV of SMGRKO mice (P<0.001); spironolactone treatment reduced the magnitude of this genotypic difference. Although spironolactone did not prevent the increase in LV levels of mRNA encoding MR or profibrotic factors (connective tissue growth factor, collagen1α2 and collagen3α1) in SMGRKO mice, it did attenuate collagen1α2 mRNA increases (P<0.05).
In conclusion, the modulatory effects of spironolactone on pro-fibrotic signalling suggest that elevated MR contributes to the pro-fibrotic cardiac phenotype discovered in SMGRKO mice. Consequently, MR antagonism may benefit individuals with particular variants of the GR gene. Spironolactone effects on heart weight indicate a role for MR in early life cardiac growth and SMGRKO mice are, potentially, a useful new model to investigate MR-dependent cardiac fibrosis.