The detrimental effects of glucocorticoids exposure during pregnancy on offspring’s cardiac functions mediated by hypermethylation of bone morphogenetic protein-4

The intra-uterine and external environmental factors not only affect the early development of fetuses, their interaction with genesis will also substantially program the physiological functions of offspring throughout life. Synthetic glucocorticoid (GC) is widely used for the management of women at risk of preterm birth or undergone autoimmune diseases. However, excess GC might cause a number of chronic diseases in later life. In the present study, we set up a programming rat model by daily injection of dexamethasone (DEX) since 14.5 dpc until labor, and found that the cardiac functions were significantly compromised in the male offspring compared with that exposed to NS, especially after ischemia/reperfusion (I/R), due to the increased infarction and apoptosis of myocardium. Using MeDIP sequencing, we identified four genes involved in the cardiac muscle cell differentiation and development pathway exhibited increased methylation in their promoter regions, among which, bone morphogenetic protein-4 (BMP4) expression is coordinately decreased in myocardium from male mice prenatally exposed to DEX. The programming effect of DEX on cardiomyocytes apoptosis was found to be dependent on mitochondria dysfunction, whereas the breakdown of mitochondrial membrane potential (ΔΨm) and the decrease of ATP production from mitochondria caused by prenatal DEX exposure both can be restored by BMP4 predisposing on neonatal cardiomyocytes 24 h prior to I/R. Inversely consistent with ΔΨm and ATP production, the release of reactive oxygen species was dramatically elevated in cardiomyocytes, which was significantly inhibited in the presence of BMP4 prior to I/R. These findings suggested that the excess GC exposure during pregnancy increases the susceptibility of male offspring’s heart to “second strike”, due to the decrease of BMP4 expression caused by the hypermethylation on Bmp4 promoter and the absence of BMP4 protective effect in cardiomyocytes, making the addition of BMP4 a promising treatment for the congenital heart disease under such circumstances.