TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner

• Published in: Genes 2023-02, Vol.14 (3), p.591
• Main Authors: Cheng, Hao, Li, Linnan, Xue, Junqiang, Ma, Jianying, Ge, Junbo
• Format: Article
• Language: English
• Subjects: Acids; Animals; Apoptosis; Biomarkers; Cardiac function; Cardiomyocytes; Congestive heart failure; Development and progression; Estrogens; Ethanol; Extracellular matrix; Extracellular Matrix - metabolism; Fibrosis; Genetic aspects; Glycoproteins; Health aspects; Heart attacks; Heart diseases; Heart failure; Heart Injuries - metabolism; Heart Injuries - pathology; Hypoxia; Hypoxia - complications; Hypoxia - metabolism; Laboratory animals; Messenger RNA; Methyltransferases; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; mRNA stability; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocytes, Cardiac - metabolism; N6-methyladenosine; Physiology; RNA modification; RNA, Messenger - genetics; RNA, Messenger - metabolism; Software; Tenascin; Tenascin - genetics; Tenascin C
• ISSN: 2073-4425; 2073-4425
• 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 m A regulator, METTL3 binds m 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 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 A levels of TNC mRNA and promoted TNC mRNA stability. Then, we mutated one m 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 A levels of TNC mRNA and may be a promising target for the therapy of cardiac fibrosis after MI.