期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 166, 期 -, 页码 91-106出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2022.02.006
关键词
Cardiomyocytes; Heart regeneration; Phosphoproteomics; MNK2; eIF4E; Cyclin D1
资金
- National Natural Science Foundation of China [82070367]
- National Key Research and Development Program of China [2016YFA0201304]
- Jiangsu Provincial Medical Innovation Team [CXTDA2017012]
- Scientific Research Innovation Projects of Graduate Students in Jiangsu Province [KYCX19_1156, KYCX20_1399]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) [KYZZ15_0263]
- Jiangsu Province Collaborative Innovation Center for Cardiovascular Disease Translational Medicine
Adult mammals have limited cardiac regeneration potential after injury, while neonatal mouse hearts can completely regenerate within 7 days of birth. This study demonstrated the critical role of mitogen-activated protein kinase-interacting serine/threonine-protein kinase 2 (MNK2) in cardiac regeneration, promoting cardiomyocyte proliferation through activation of the eIF4E-cyclin D1 axis.
Adult mammals have limited potential for cardiac regeneration after injury. In contrast, neonatal mouse heart, up to 7 days post birth, can completely regenerate after injury. Therefore, identifying the key factors promoting the proliferation of endogenous cardiomyocytes (CMs) is a critical step in the development of cardiac regeneration therapies. In our previous study, we predicted that mitogen-activated protein kinase (MAPK) interacting serine/threonine-protein kinase 2 (MNK2) has the potential of promoting regeneration by using phosphoproteomics and iGPS algorithm. Here, we aimed to clarify the role of MNK2 in cardiac regeneration and explore the underlying mechanism. In vitro, MNK2 overexpression promoted, and MNK2 knockdown suppressed cardiomyocyte proliferation. In vivo, inhibition of MNK2 in CMs impaired myocardial regeneration in neonatal mice. In adult myocardial infarcted mice, MNK2 overexpression in CMs in the infarct border zone activated cardiomyocyte proliferation and improved cardiac repair. In CMs, MNK2 binded to eIF4E and regulated its phosphorylation level. Knockdown of eukaryotic translation initiation factor (eIF4E) impaired the proliferation promoting effect of MNK2 in CMs. MNK2-eIF4E axis stimulated CMs proliferation by activating cyclin D1. Our study demonstrated that MNK2 kinase played a critical role in cardiac regeneration. Over-expression of MNK2 promoted cardiomyocyte proliferation in vitro and in vivo, at least partly, by activating the eIF4E-cyclin D1 axis. This investigation identified a novel target for heart regenerative therapy.
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