Yap Contributes to Cardiomyocyte Proliferation in the Fetal Rat Heart Epicardium with Antenatal Glucocorticoid Administration

Background: Our previous reports demonstrated that antenatal glucocorticoid (GC) administration increased cardiomyocyte proliferation in preterm fetuses, leading to the maturation of the heart. Understanding the proliferative mechanisms of fetal cardiomyocytes might be applicable to regenerative therapeutic strategies. In this study, we investigated whether antenatal GC administration affects Yes-associated protein (Yap), a transcriptional activator of cardiomyocyte proliferation.Methods and Results: Eight-week-old pregnant Wistar rats were administered dexamethasone for 2 consecutive days between gestational days 17 and 21 before cesarean section. The production of the proliferation markers, cyclin D1, Ki-67, and Yap in the nuclei of cardiomyocytes was analyzed using immunohistochemistry. To clarify the relationship between upstream factors and Yap, we evaluated the expression of agrin, an extracellular matrix protein, using Western blot analysis. Although cyclin D1-, Ki-67-, and Yap-positive cells gradually decreased from the fetal to neonatal stage, they increased significantly in the epicardium of 19-day fetal groups with antenatal GC administration. Agrin was also significantly increased in fetal hearts in the GC group.Conclusions: These results suggest that antenatal GC administration affects cell proliferation in the fetal epicardium, and the increased agrin and Yap activation may be involved.