AIMS: N-methyladenosine (mA) is the most prevalent internal chemical RNA modification in mammal mRNAs. Accumulating evidence has shown the critical role of mA in cardiovascular diseases including cardiac hypertrophy, heart failure, ischemic heart disease, vascular calcification, restenosis, and aortic aneurysm. However, whether mA participates in the occurrence and development of hypoxic pulmonary hypertension (HPH) remains largely unknown. The present study aims to explore the role of key transferase METTL3, in the development of HPH. 6 6 6 6
MATERIALS AND METHODS: Pulmonary artery smooth muscle cells (PASMCs) and hypoxic rat models were used to research the METTL3-mediated mA in HPH. EdU, transwell and TUNEL were performed to evaluate the proliferation, migration and apoptosis rates. mA RNA Methylation Quantification Kit and mA-qPCR were utilized to measure the total mA level and mA level of PTEN mRNA. RNA immunoprecipitation was used to detect the interaction between METTL3 and PTEN mRNA. 6 6 6 6 6
KEY FINDINGS: Both METTL3 mRNA and protein were found abnormally upregulated in vivo and in vitro. Furthermore, downregulation of METTL3 attenuated PASMCs proliferation and migration. In addition, mA binding protein YTHDF2 was found significantly increased in PASMCs under hypoxia. YTHDF2 recognized METTL3 mediated mA modified PTEN mRNA and promoted the degradation of PTEN. Decreased PTEN led to over-proliferation of PASMCs through activation of PI3K/Akt signaling pathway. 6 6
SIGNIFICANCE: METTL3/YTHDF2/PTEN axis exerts a significant role in hypoxia induced PASMCs proliferation, providing a novel therapeutic target for HPH.
