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Background: Hypoxia causes oxidative stress and affects cardiovascular function and theprogramming of cardiovascular disease. Melatonin promotes antioxidant enzymes such assuperoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase. Objectives: This study aims to investigate the correlation between melatonin and hypoxiainduction in cardiomyocytes differentiation. Methods: Mouse embryonic stem cells (mESCs) were induced to myocardial differentiation. To demonstrate the influence of melatonin under hypoxia, mESC was pretreated withmelatonin and then cultured in hypoxic condition. The cardiac beating ratio of the mESCderivedcardiomyocytes, mRNA and protein expression levels were investigated. Results: Under hypoxic condition, the mRNA expression of cardiac-lineage markers(Brachyury, Tbx20, and cTn1) and melatonin receptor (Mtnr1a) was reduced. The mRNAexpression of cTn1 and the beating ratio of mESCs increased when melatonin was treatedsimultaneously with hypoxia, compared to when only exposed to hypoxia. Hypoxia-induciblefactor (HIF)-1α protein decreased with melatonin treatment under hypoxia, and Mtnr1amRNA expression increased. When the cells were exposed to hypoxia with melatonintreatment, the protein expressions of phospho-extracellular signal-related kinase (p-ERK)and Bcl-2-associated X proteins (Bax) decreased, however, the levels of phospho-proteinkinase B (p-Akt), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (Bcl-2) proteins,and antioxidant enzymes including Cu/Zn-SOD, Mn-SOD, and catalase were increased. Competitive melatonin receptor antagonist luzindole blocked the melatonin-induced effects. Conclusions: This study demonstrates that hypoxia inhibits cardiomyocytes differentiationand melatonin partially mitigates the adverse effect of hypoxia in myocardial differentiationby regulating apoptosis and oxidative stress through the p-AKT and PI3K pathway.
