The detrimental effects of glucocorticoids exposure during pregnancy on offspring\u2019s cardiac functions mediated by hypermethylation of bone morphogenetic protein-4

Jieying Peng,Zhiming Wang,Xiao Zhang,Lu Gao,Hongxing Yang,Huaiyan Chen,Yuhao Zhou,Zhiyu Zhang,Zhou Fang,Guangyao Li,Lingtong Gao

doi:10.1038/s41419-018-0841-1

Abstract

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.

Highlights

Medical University, Shanghai 200433, China 2Department of Health Management, Changzheng Hospital, Second MilitaryMedical University, Shanghai 200003, ChinaFull list of author information is available at the end of the article.The intra-uterine and external environmental factors affect the early development of fetuses, their interaction with genesis will substantially program the physiological functions of offspring throughout life[1]
It was found that the Left ventricular ejection fraction (LVEF) and Left ventricular fractional shortening (LVFS) of male offspring exposed to DEX during late gestation were significantly decreased, which was not observed in female offspring (Figs. 1b-e)
To further confirm the changes of cardiac functions, we determined the maximal rate of left ventricle systolic pressure change ( + dp/dt max) and the maximal rate of left ventricle diastolic pressure change (–dp/dt max) of adult offspring using heart floating catheter, and no significant differences were shown between normal saline (NS) group and DEX group (Figs. 1f, h)

Summary

Introduction

Medical University, Shanghai 200433, China 2Department of Health Management, Changzheng Hospital, Second MilitaryMedical University, Shanghai 200003, ChinaFull list of author information is available at the end of the article.The intra-uterine and external environmental factors affect the early development of fetuses, their interaction with genesis will substantially program the physiological functions of offspring throughout life[1]. Since Barkers et al found the association of adverse intra-. These authors contributed : Jieying Peng, Yuhao Zhou and Zhiyu Zhang Edited by Y. Peng et al Cell Death and Disease (2018)9:834 uterine environment with an increased risk of hypertension and ischemic heart disease in adulthood[2], a large number of findings in many species have demonstrated that neurological, endocrine, metabolic and cardiovascular function and dysfunction in adulthood have developmental origins[3,4,5]. The maternal chronic hypoxia during late gestation could increase the cardiac vulnerability to ischemia and reperfusion injury in adult offspring in rats via downregulating the expression of PKC {epsilon} (protein kinase C epsilon) in myocardium[6]. Fetal undernutrition in utero by maternal food restriction significantly increases angiotensinogen and endothelin-1 expression in the left ventricles of adult offspring, which subsequently causes the increase in systolic blood pressure, perivascular fibrosis of the coronary artery, cardiac cardiomegaly and cardiomyocyte enlargement[7]

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Conclusion