Glucocorticoids rapidly promote YAP phosphorylation via the cAMP-PKA pathway to repress mouse cardiomyocyte proliferative potential

Abstract

Adult mammalian cardiomyocytes (CMs) lose their proliferative potential due to cell-cycle withdrawal and polyploidization and fail to mount a proliferative response to regenerate new CMs after cardiac injury. The decline in the proliferative potential of mammalian CMs occurs in the neonatal period when the endocrine system undergoes drastic changes for adaptation to extra-uterine life. There is an increase in circulating glucocorticoid (GC) levels shortly after birth in mammals, and thus, we sought to determine the roles and mechanisms of GCs in regulating CM proliferation. Here, we showed that GCs suppressed CM proliferation in vitro and in vivo, decreased the total number of CMs, and increased the cross-sectional area of CMs. However, the glucocorticoid receptor antagonist had no effect on CM proliferation. Agonists of adenylate cyclase and protein kinase A (PKA) inhibited CM proliferation, while PKA antagonists or knockdown of PKA alleviated the inhibitory effect of GCs on CM proliferation. GCs and the activation of the cyclic adenosine monophosphate (cAMP)/PKA signaling pathway facilitated yes-associated protein (YAP) phosphorylation in mouse CMs and promoted YAP protein translocation from the nucleus to the cytoplasm. Meanwhile, blocking the cAMP/PKA signaling pathway partially blocked the effect of GCs on YAP protein phosphorylation and YAP protein translocation. Thus, our findings suggest that GCs suppress mouse CM proliferation in vitro and in vivo, through a mechanism that involves targeting the cAMP-PKA-YAP signaling pathway.