Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
Genes (Basel). 2023 Feb 26;14(3):591. doi: 10.3390/genes14030591.
Cardiac fibrosis and cardiomyocyte apoptosis are reparative processes after myocardial infarction (MI), which results in cardiac remodeling and heart failure at last. Tenascin-C (TNC) consists of four distinct domains, which is a large multimodular glycoprotein of the extracellular matrix. It is also a key regulator of proliferation and apoptosis in cardiomyocytes. As a significant mA regulator, METTL3 binds mA sites in mRNA to control its degradation, maturation, stabilization, and translation. Whether METTL3 regulates the occurrence and development of myocardial infarction through the mA modification of TNC mRNA deserves our study. Here, we have demonstrated that overexpression of METTL3 aggravated cardiac dysfunction and cardiac fibrosis after 4 weeks after MI. Moreover, we also demonstrated that TNC resulted in cardiac fibrosis and cardiomyocyte apoptosis after MI. Mechanistically, METTL3 led to enhanced mA levels of TNC mRNA and promoted TNC mRNA stability. Then, we mutated one mA site "A" to "T", and the binding ability of METTL3 was reduced. In conclusion, METTL3 is involved in cardiac fibrosis and cardiomyocyte apoptosis by increasing mA levels of TNC mRNA and may be a promising target for the therapy of cardiac fibrosis after MI.
心肌纤维化和心肌细胞凋亡是心肌梗死后的修复过程，最终导致心脏重构和心力衰竭。Tenascin-C（TNC）由四个不同的结构域组成，是细胞外基质中的一种大型多功能糖蛋白。它也是心肌细胞增殖和凋亡的关键调节因子。作为一个重要的 mA 调节因子，METTL3 通过结合 mRNA 中的 mA 位点来控制其降解、成熟、稳定和翻译。METTL3 是否通过 TNC mRNA 的 mA 修饰来调节心肌梗死的发生和发展值得我们研究。在这里，我们已经证明，METTL3 的过表达在心肌梗死后 4 周时加重了心脏功能障碍和心脏纤维化。此外，我们还证明 TNC 在心肌梗死后导致心脏纤维化和心肌细胞凋亡。从机制上讲，METTL3 通过增加 TNC mRNA 的 mA 水平导致 TNC mRNA 的稳定性增强。然后，我们将一个 mA 位点“ A”突变为“ T”，METTL3 的结合能力降低。总之，METTL3 通过增加 TNC mRNA 的 mA 水平参与心肌纤维化和心肌细胞凋亡，可能是心肌梗死后心脏纤维化治疗的有希望的靶点。
