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Melatonin promotes cardiomyocyte proliferation and heart repair in mice with myocardial infarction via miR-143-3p/Yap/Ctnnd1 signaling pathway
- Source :
- Acta Pharmacol Sin
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- 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 (1 μM) 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.
- Subjects :
- 0301 basic medicine
Delta Catenin
Myocardial Infarction
medicine.disease_cause
Melatonin receptor
Article
Melatonin
03 medical and health sciences
0302 clinical medicine
medicine
Animals
Regeneration
Myocytes, Cardiac
Pharmacology (medical)
Cells, Cultured
Adaptor Proteins, Signal Transducing
Cell Proliferation
Pharmacology
Receptor, Melatonin, MT2
Chemistry
Myocardium
Receptor, Melatonin, MT1
Cell Cycle
Catenins
Heart
YAP-Signaling Proteins
General Medicine
Cell cycle
Cell biology
Mice, Inbred C57BL
MicroRNAs
030104 developmental biology
Animals, Newborn
Apoptosis
030220 oncology & carcinogenesis
Mitochondrial fission
Signal transduction
Luzindole
Oxidative stress
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 17457254 and 16714083
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....b8d71d3858086ca2d8914d18787522b6
- Full Text :
- https://doi.org/10.1038/s41401-020-0495-2