Melatonin promotes cardiomyocyte proliferation and heart repair in mice with myocardial infarction via miR-143-3p/Yap/Ctnnd1 signaling pathway  

作　　者：Wen-ya Ma Rui-jie Song Bin-bin Xu Yan Xu Xiu-xiu Wang Hong-yue Sun Shuai-nan Li Shen-zhen Liu Mei-xi Yu Fan Yang Dan-yu Ye Rui Gong Zhen-bo Han Ying Yu Djibril Bamba Ning Wang Zhen-wei Pan Ben-zhi Cai 

机构地区：[1]Department of Pharmacy at The Second Affiliated Hospital,and Department of Pharmacology at College of Pharmacy(The Key Laboratory of Cardiovascular Medicine Research,Ministry of Education),Harbin Medical University,Harbin 150086,China [2]Institute of Clinical Pharmacy,the Heilongjiang Key Laboratory of Drug Research,Harbin Medical University,Harbin 150086,China [3]Research Unit of Noninfectious Chronic Diseases in Frigid Zone,Chinese Academy of Medical Sciences,Harbin 150086,China

出　　处：《Acta Pharmacologica Sinica》2021年第6期921-931,共11页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China[81872857,81573434,81170096,81773733];the China Postdoctoral Science Foundation[2018M641867];the Heilongjiang Postdoctoral Fund[LBH-Z18126].

摘　　要：The neonatal heart possesses the ability to proliferate and the capacity to regenerate after injury;however,the mechanisms underlying these processes are not fully understood.Melatonin has been shown to protect the heart against myocardial injury through mitigating oxidative stress,reducing apoptosis,inhibiting mitochondrial fission,etc.In this study,we investigated whether melatonin regulated cardiomyocyte proliferation and promoted cardiac repair in mice with myocardial infarction(MI),which was induced by ligation of the left anterior descending coronary artery.We showed that melatonin administration significantly improved the cardiac functions accompanied by markedly enhanced cardiomyocyte proliferation in MI mice.In neonatal mouse cardiomyocytes,treatment with melatonin(1μM)greatly suppressed miR-143-3p levels.Silencing of miR-143-3p stimulated cardiomyocytes to re-enter the cell cycle.On the contrary,overexpression of miR-143-3p inhibited the mitosis of cardiomyocytes and abrogated cardiomyocyte mitosis induced by exposure to melatonin.Moreover,Yap and Ctnnd1 were identified as the target genes of miR-143-3p.In cardiomyocytes,inhibition of miR-143-3p increased the protein expression of Yap and Ctnnd1.Melatonin treatment also enhanced Yap and Ctnnd1 protein levels.Furthermore,Yap siRNA and Ctnnd1 siRNA attenuated melatonin-induced cell cycle re-entry of cardiomyocytes.We showed that the effect of melatonin on cardiomyocyte proliferation and cardiac regeneration was impeded by the melatonin receptor inhibitor luzindole.Silencing miR-143-3p abrogated the inhibition of luzindole on cardiomyocyte proliferation.In addition,both MT1 and MT2 siRNA could cancel the beneficial effects of melatonin on cardiomyocyte proliferation.Collectively,the results suggest that melatonin induces cardiomyocyte proliferation and heart regeneration after MI by regulating the miR-143-3p/Yap/Ctnnd1 signaling pathway,providing a new therapeutic strategy for cardiac regeneration.

关 键 词：MELATONIN LUZINDOLE cardiomyocyte proliferation cardiac repair miR-143-3p Yap Ctnnd1 myocardial infarction 

分 类 号：R285.5[医药卫生—中药学]