Abstract
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 m(6)A regulator, METTL3 binds m(6)A sites in mRNA to control its degradation, maturation, stabilization, and translation. Whether METTL3 regulates the occurrence and development of myocardial infarction through the m(6)A 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 m(6)A levels of TNC mRNA and promoted TNC mRNA stability. Then, we mutated one m(6)A 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 m(6)A levels of TNC mRNA and may be a promising target for the therapy of cardiac fibrosis after MI.