Antenatal Glucocorticoid Administration Promotes Cardiac Structure and Energy Metabolism Maturation in Preterm Fetuses

Abstract

Although the rate of preterm birth has increased in recent decades, a number of preterm infants have escaped death due to improvements in perinatal and neonatal care. Antenatal glucocorticoid (GC) therapy has significantly contributed to progression in lung maturation; however, its potential effects on other organs remain controversial. Furthermore, the effects of antenatal GC therapy on the fetal heart show both pros and cons. Translational research in animal models indicates that constant fetal exposure to antenatal GC administration is sufficient for lung maturation. We have established a premature fetal rat model to investigate immature cardiopulmonary functions in the lungs and heart, including the effects of antenatal GC administration. In this review, we explain the mechanisms of antenatal GC actions on the heart in the fetus compared to those in the neonate. Antenatal GCs may contribute to premature heart maturation by accelerating cardiomyocyte proliferation, angiogenesis, energy production, and sarcoplasmic reticulum function. Additionally, this review specifically focuses on fetal heart growth with antenatal GC administration in experimental animal models. Moreover, knowledge regarding antenatal GC administration in experimental animal models can be coupled with that from developmental biology, with the potential for the generation of functional cells and tissues that could be used for regenerative medical purposes in the future.

Keywords: antenatal glucocorticoid; cardiac growth; fetal heart.

Figure 1

Schematic diagram of cell proliferation and angiogenesis. Pregnant rats are administered glucocorticoids (GCs) subcutaneously for two days, on gestational days 17 and 19, and fetuses are delivered by cesarean section. On histological analysis, the cross-sectional area of the myocardium is smaller in 19-day-old fetuses than in neonates. Physiological hypertrophy is induced by cardiac cell proliferation and angiogenesis. Antenatal GC administration enhances phosphatidylinositol-3 kinase (PI3K), which activates Akt-1. Moreover, Akt-1 accelerates both phosphorylated glycogen synthase kinase-3β (p-GSK-3β) and vascular endothelial growth factor (VEGF) expression. Subsequently, p-GSK-3β contributes to the activation of cardiomyocyte proliferation factors, β-catenin, Yes-associated protein (Yap), and GATA-4. Accordingly, cell proliferation markers, Ki-67 and cyclin D1, are increased in the nuclei of fetal cardiomyocytes. GATA binding protein, GATA.

Figure 2

Schematic diagram of energy production and acceleration of cardiac contraction. Energy metabolism in the fetal heart is relatively dependent on anaerobic glycolysis. α-Enolase converts glucose into pyruvate. Energy released during glycolysis is used to make ATP, and antenatal glucocorticoid (GC) administration accelerates these pathways. Furthermore, antenatal GC administration induces creatine kinase (CK) protein production by promoting myofibrillar-bound M isoenzyme CK (CK-M) and mitochondrial CK (Mi-CK) gene expression in the mitochondria. Increased CK-M and Mi-CK enzymes contribute to increased ATP synthesis. Cardiac energy metabolism is essential for normal cardiac contractile function. GATA-4 has not only involvement in cell proliferation but also in binding the cells to the troponin T promoter. Antenatal GC increases the expression of GATA-4, troponin T, SERCA2a, and phospholamban. Cardiac contraction is increased with the increase in intracellular Ca²⁺ concentration and troponin T expression. SERCA2a plays a crucial role in the regulation of the intracellular Ca²⁺ concentration in the SR. Ca²⁺ enters myocytes during an action potential through voltage-gated Ca²⁺ channels in the sarcolemma. This Ca²⁺ influx triggers the release of Ca²⁺ from the SR by RyR2, which increases the intracellular Ca²⁺ concentration, resulting in myocardial contraction. Sarco-endoplasmic reticulum Ca-ATPase, SERCA; sarcoendoplasmic reticulum, SR; ryanodine receptor, RyR.