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 this study, by employing differentiating mouse embryonic stem cells, we report that melatonin significantly upregulated the expression of cardiac cell-specific markers (myosin heavy chains six and seven) as well as the percentage of myosin heavy chain-positive cells. Importantly, melatonin decreased HIF-1α stabilization and transcriptional activity and, in contrast, induced HIF-2α stabilization. Interestingly, the deletion of HIF-1α completely inhibited the pro-cardiomyogenic effect of melatonin as well as the melatonin-mediated HIF-2α stabilization. Moreover, melatonin increased Sirt-1 levels in a HIF-1α-dependent manner. Taken together, we provide new evidence of a time-specific inhibition of HIF-1α 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.
Institute of Biophysics, Czech Academy of Sciences, Brno, Czech Republic.|Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
Jana
J
Kudová
Institute of Biophysics, Czech Academy of Sciences, Brno, Czech Republic.|International Clinical Research Center, Centre of Biomolecular and Cellular Engineering, St. Anne's University Hospital, Brno, Czech Republic.
Ondřej
O
Vašíček
Institute of Biophysics, Czech Academy of Sciences, Brno, Czech Republic.
Milan
M
Číž
Institute of Biophysics, Czech Academy of Sciences, Brno, Czech Republic. kubalal@ibp.cz.|International Clinical Research Center, Centre of Biomolecular and Cellular Engineering, St. Anne's University Hospital, Brno, Czech Republic. kubalal@ibp.cz.
Lukáš
L
Kubala
D000818:Animals; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D024510:Muscle Development / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008550:Melatonin
cardiomyogenesis; hypoxia-inducible factor-alpha; melatonin; mouse embryonic stem cells