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http://dx.doi.org/10.4142/jvs.2021.22.e54

Melatonin mitigates the adverse effect of hypoxia during myocardial differentiation in mouse embryonic stem cells  

Lee, Jae-Hwan (Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University)
Yoo, Yeong-Min (Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University)
Lee, Bonn (Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University)
Jeong, SunHwa (Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University)
Tran, Dinh Nam (Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University)
Jeung, Eui-Bae (Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University)
Publication Information
Journal of Veterinary Science / v.22, no.4, 2021 , pp. 54.1-54.13 More about this Journal
Abstract
Background: Hypoxia causes oxidative stress and affects cardiovascular function and the programming of cardiovascular disease. Melatonin promotes antioxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione peroxidase, and catalase. Objectives: This study aims to investigate the correlation between melatonin and hypoxia induction 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 with melatonin and then cultured in hypoxic condition. The cardiac beating ratio of the mESC-derived cardiomyocytes, 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 mRNA expression of cTn1 and the beating ratio of mESCs increased when melatonin was treated simultaneously with hypoxia, compared to when only exposed to hypoxia. Hypoxia-inducible factor (HIF)-1α protein decreased with melatonin treatment under hypoxia, and Mtnr1a mRNA expression increased. When the cells were exposed to hypoxia with melatonin treatment, the protein expressions of phospho-extracellular signal-related kinase (p-ERK) and Bcl-2-associated X proteins (Bax) decreased, however, the levels of phospho-protein kinase 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 differentiation and melatonin partially mitigates the adverse effect of hypoxia in myocardial differentiation by regulating apoptosis and oxidative stress through the p-AKT and PI3K pathway.
Keywords
Melatonin; hypoxia; cardiomyocytes; mESCs; Apoptosis;
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1 Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59(4):403-419.   DOI
2 Richter HG, Hansell JA, Raut S, Giussani DA. Melatonin improves placental efficiency and birth weight and increases the placental expression of antioxidant enzymes in undernourished pregnancy. J Pineal Res. 2009;46(4):357-364.   DOI
3 Hu S, Zhu P, Zhou H, Zhang Y, Chen Y. Melatonin-induced protective effects on cardiomyocytes against reperfusion injury partly through modulation of IP3R and SERCA2a via activation of ERK1. Arq Bras Cardiol. 2018;110(1):44-51.
4 Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L. Beneficial effects of melatonin in cardiovascular disease. Ann Med. 2010;42(4):276-285.   DOI
5 Nduhirabandi F, Maarman GJ. Melatonin in heart failure: a promising therapeutic strategy? Molecules. 2018;23(7):1819.   DOI
6 Shi L, Liang F, Zheng J, Zhou K, Chen S, Yu J, et al. Melatonin regulates apoptosis and autophagy via ROSMST1 pathway in subarachnoid hemorrhage. Front Mol Neurosci. 2018;11:93.   DOI
7 Lee SJ, Lee HJ, Jung YH, Kim JS, Choi SH, Han HJ. Melatonin inhibits apoptotic cell death induced by Vibrio vulnificus VvhA via melatonin receptor 2 coupling with NCF-1. Cell Death Dis. 2018;9(2):48.   DOI
8 Sarker U, Oba S. Catalase, superoxide dismutase and ascorbate-glutathione cycle enzymes confer drought tolerance of Amaranthus tricolor. Sci Rep. 2018;8(1):16496.   DOI
9 Lee JG, Woo YS, Park SW, Seog DH, Seo MK, Bahk WM. The neuroprotective effects of melatonin: possible role in the pathophysiology of neuropsychiatric disease. Brain Sci. 2019;9(10):285.   DOI
10 Lipartiti M, Franceschini D, Zanoni R, Gusella M, Giusti P, Cagnoli CM, et al. Neuroprotective effects of melatonin. Adv Exp Med Biol. 1996;398:315-321.   DOI
11 Zhou T, Chuang CC, Zuo L. Molecular characterization of reactive oxygen species in myocardial ischemia-reperfusion injury. BioMed Res Int. 2015;2015:864946.   DOI
12 Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. International union of basic and clinical pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev. 2010;62(3):343-380.   DOI
13 Barker DJ, Osmond C, Simmonds SJ, Wield GA. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ. 1993;306(6875):422-426.   DOI
14 Akira M, Yoshiyuki S. Placental circulation, fetal growth, and stiffness of the abdominal aorta in newborn infants. J Pediatr. 2006;148(1):49-53.   DOI
15 Rajala K, Pekkanen-Mattila M, Aalto-Setala K. Cardiac differentiation of pluripotent stem cells. Stem Cells Int. 2011;2011:383709.   DOI
16 Zhang HM, Zhang Y. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res. 2014;57(2):131-146.   DOI
17 Cui P, Yu M, Luo Z, Dai M, Han J, Xiu R, et al. Intracellular signaling pathways involved in cell growth inhibition of human umbilical vein endothelial cells by melatonin. J Pineal Res. 2008;44(1):107-114.   DOI
18 Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36(1):1-9.   DOI
19 Nah SS, Won HJ, Park HJ, Ha E, Chung JH, Cho HY, et al. Melatonin inhibits human fibroblast-like synoviocyte proliferation via extracellular signal-regulated protein kinase/P21(CIP1)/P27(KIP1) pathways. J Pineal Res. 2009;47(1):70-74.   DOI
20 Grutzner U, Keller M, Bach M, Kiemer AK, Meissner H, Bilzer M, et al. PI 3-kinase pathway is responsible for antiapoptotic effects of atrial natriuretic peptide in rat liver transplantation. World J Gastroenterol. 2006;12(7):1049-1055.   DOI
21 Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. 2001;26(11):657-664.   DOI
22 Guerra-Librero A, Fernandez-Gil BI, Florido J, Martinez-Ruiz L, Rodriguez-Santana C, Shen YQ, et al. Melatonin targets metabolism in head and neck cancer cells by regulating mitochondrial structure and function. Antioxidants. 2021;10(4):603.   DOI
23 Kudova J, Vasicek O, Ciz M, Kubala L. Melatonin promotes cardiomyogenesis of embryonic stem cells via inhibition of HIF-1α stabilization. J Pineal Res. 2016;61(4):493-503.   DOI
24 Kim CW, Go RE, Ko EB, Jeung EB, Kim MS, Choi KC. Effects of cigarette smoke components on myocardial differentiation of mouse embryonic stem cells. Environ Toxicol. 2020;35(1):66-77.   DOI
25 Migdal C, Serres M. Reactive oxygen species and oxidative stress. Med Sci (Paris). 2011;27(4):405-412.   DOI
26 Jiki Z, Lecour S, Nduhirabandi F. Cardiovascular benefits of dietary melatonin: a myth or a reality? Front Physiol. 2018;9:528.   DOI
27 Han D, Wang Y, Chen J, Zhang J, Yu P, Zhang R, et al. Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin-conferred cardioprotection against myocardial ischemia/reperfusion injury. J Pineal Res. 2019;67(1):e12571.   DOI
28 Itani N, Skeffington KL, Beck C, Niu Y, Giussani DA. Melatonin rescues cardiovascular dysfunction during hypoxic development in the chick embryo. J Pineal Res. 2016;60(1):16-26.   DOI
29 Fruehauf JP, Meyskens FL Jr. Reactive oxygen species: a breath of life or death? Clin Cancer Res. 2007;13(3):789-794.   DOI
30 Bongiovanni B, De Lorenzi P, Ferri A, Konjuh C, Rassetto M, Evangelista de Duffard AM, et al. Melatonin decreases the oxidative stress produced by 2,4-dichlorophenoxyacetic acid in rat cerebellar granule cells. Neurotox Res. 2007;11(2):93-99.   DOI
31 Lee JH, Yoo YM, Jung EM, Ahn CH, Jeung EB. Inhibitory effect of octyl-phenol and bisphenol A on calcium signaling in cardiomyocyte differentiation of mouse embryonic stem cells. J Physiol Pharmacol. 2019;70(3):435-442.
32 Reiter RJ, Paredes SD, Manchester LC, Tan DX. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol. 2009;44(4):175-200.   DOI
33 Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61-73.   DOI
34 Zhang L. Prenatal hypoxia and cardiac programming. J Soc Gynecol Investig. 2005;12(1):2-13.   DOI
35 Williams SJ, Hemmings DG, Mitchell JM, McMillen IC, Davidge ST. Effects of maternal hypoxia or nutrient restriction during pregnancy on endothelial function in adult male rat offspring. J Physiol. 2005;565(Pt 1):125-135.   DOI
36 Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 2005;115(3):500-508.   DOI
37 Giussani DA, Spencer JA, Moore PJ, Bennet L, Hanson MA. Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. J Physiol. 1993;461(1):431-449.   DOI
38 Kurian GA, Rajagopal R, Vedantham S, Rajesh M. The role of oxidative stress in myocardial ischemia and reperfusion injury and remodeling: revisited. Oxid Med Cell Longev. 2016;2016:1656450.   DOI
39 Hesse M, Welz A, Fleischmann BK. Heart regeneration and the cardiomyocyte cell cycle. Pflugers Arch. 2018;470(2):241-248.   DOI
40 Reiter RJ, Tan DX, Jou MJ, Korkmaz A, Manchester LC, Paredes SD. Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites. Neuroendocrinol Lett. 2008;29(4):391-398.