Glucocorticoid signalling is essential for cardiac maturation late gestation. In mice, global glucocorticoid receptor deficiency (GR−/−) severely impairs cardiac function and ultrastructure at embryonic day (E) 17.5. To dissect direct effects of GR deficiency in the heart from effects on other systems, Sm22α-Cre mice were crossed with floxed GR mice to generate SMGRKO mice with disrupted GR signalling in cardiomyocytes and vascular smooth muscle cells. GR mRNA and protein levels in hearts of fetal SMGRKO mice are reduced by ~65%, without any change in other organs (liver, kidney, lung) or in plasma corticosterone levels.
In contrast to global GR-deficiency, late gestation SMGRKO mice are viable but still show oedema. In vivo ultrasound analysis showed impaired heart function with elevated myocardial performance index (MPI) in SMGRKO compared to floxed littermate controls (SMGRKO 0.43±0.01 vs control 0.49±0.2, n=2026, P<0.05). Histopatholgy showed cardiomyocytes in SMGRKO fetuses are irregularily shaped and smaller than in controls, and fail to align in the outermost layer of the compact myocardium. Electron microscopy revealed immature and disorganised myofibrils in SMGRKO cardiomyocytes, similar to global GR-deficiency. SMGRKO hearts showed mRNA changes indicating reduced contraction (Myosin Heavy Chain-α), energy metabolism (hexokinase-1, PGC-1α) and calcium handling (Cav1.2, RyR2, SERCA2a) in SMGRKO at E17.5.
Thus, the cardiac phenotype of SMGRKO fetuses is strikingly similar to that of global GR-deficienct, albeit of lesser magnitude owing perhaps to incomplete GR deletion in the heart. However, in contrast to the smaller hearts of globally GR-deficient fetuses, hearts of E17.5 SMGRKO mice are normally sized. This suggests that smaller hearts in global GR-deficiency is secondary to lack of GR elsewhere.
These data support a role for GR within cardiomyocytes in promotion of cardiac maturation.
Declaration of funding: This work was supported by the BHF scholarship to E A R-Z, FS/08 per 065.