期刊
THERANOSTICS
卷 11, 期 6, 页码 3000-3016出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.47354
关键词
Heart regeneration; cardiomyocyte proliferation; m(6)A; ALKBH5; myocardial infarction
资金
- National Key R&D Program of China [2017YFC1307403]
- National Natural Science Fund of China [81872857/81573434/81170096/81730012]
The study reveals the significant role of m(6)A RNA modification in heart regeneration, with the ALKBH5-m(6)A-YTHDF1-YAP axis regulating cardiomyocytes to re-enter the cell cycle. This finding offers a novel therapeutic strategy for cardiac regeneration.
N-6-methyladenosine (m(6)A) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis. However, the potential involvement of m(6)A in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear. In this study, we aimed to investigate the essential role of m(6)A modification in heart regeneration during postnatal and adult injury. Methods and results: In this study, we identified the downregulation of m(6)A demethylase ALKBH5, an m(6)A eraser that is responsible for increased m(6)A methylation, in the heart after birth. Notably, ALKBH5 knockout mice exhibited decreased cardiac regenerative ability and heart function after neonatal apex resection. Conversely, forced expression of ALKBH5 via adeno-associated virus-9 (AAV9) delivery markedly reduced the infarct size, restored cardiac function and promoted CM proliferation after myocardial infarction in juvenile (7 days old) and adult (8-weeks old) mice. Mechanistically, ALKBH5-mediated m(6)A demethylation improved the mRNA stability of YTH N-6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). The modulation of ALKBH5 and YTHDF1 expression in human induced pluripotent stem cell-derived cardiomyocytes consistently yielded similar results. Conclusion: Taken together, our findings highlight the vital role of the ALKBH5-m(6)A-YTHDF1-YAP axis in the regulation of CMs to re-enter the cell cycle. This finding suggests a novel potential therapeutic strategy for cardiac regeneration.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据