Melatonin promotes cardiomyogenesis of embryonic stem cells via inhibition of HIF‐1α stabilization

Melatonin, a molecule involved in the regulation of circadian rhythms, has protective effects against myocardial injuries. However, its capability to regulate the maturation of cardiac progenitor cells is unclear. Recently, several studies have shown that melatonin inhibits the stabilization of hypoxia inducible factors (HIFs), important signaling molecules with cardioprotective effects. In the present study, by employing differentiating mouse embryonic stem cells, we report that melatonin significantly upregulated the expression of cardiac cell specific markers (myosin heavy chains 6 and 7) as well as the percentage of myosin heavy chain positive cells. Importantly, melatonin decreased HIF-1alpha stabilization and transcriptional activity and, in contrast, induced HIF-2alpha stabilization. Interestingly, the deletion of HIF-1alpha completely inhibited the pro-cardiomyogenic effect of melatonin as well as the melatonin-mediated HIF-2alpha stabilization. Moreover, melatonin increased Sirt-1 levels in a HIF-1alpha dependent manner. Taken together, we provide new evidence of a time-specific inhibition of HIF-1alpha stabilization as an essential feature of melatonin-induced cardiomyogenesis and unexpected different roles of HIF-1α stabilization during various stages of cardiac development. These results uncover new mechanisms underlying the maturation of cardiac progenitor cells and can help in the development of novel strategies for using melatonin in cardiac regeneration therapy. This article is protected by copyright. All rights reserved.