Zhao Yongchao, Kong Lingqiu, Pei Zhiqiang, Li Fuhai, Li Chaofu, Sun Xiaolei, Shi Bei, Ge Junbo
Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Front Cell Dev Biol. 2021 May 31;9:642080. doi: 10.3389/fcell.2021.642080. eCollection 2021.
Post-transcriptional modifications play pivotal roles in various pathological processes and ischemic disorders. However, the role of N7-methylguanosine (m7G), particularly m7G in mRNA, on post-ischemic angiogenesis remains largely unknown. Here, we identified that methyltransferase like 1 (METTL1) was a critical candidate responsible for a global decrease of m7G within mRNA from the ischemic tissues. The gene transfer of METTL1 improved blood flow recovery and increased angiogenesis with enhanced mRNA m7G upon post-ischemic injury. Increased METTL1 expression using plasmid transfection promoted HUVECs proliferation, migration, and tube formation with a global increase of m7G in mRNA. Mechanistically, METTL1 promoted VEGFA mRNA translation in an m7G methylation-dependent manner. Our findings emphasize a critical link between mRNA m7G and ischemia and provide a novel insight of targeting METTL1 in the therapeutic angiogenesis for ischemic disorders, including peripheral arterial disease.
转录后修饰在各种病理过程和缺血性疾病中起着关键作用。然而，N7-甲基鸟苷（m7G），尤其是mRNA中的m7G，在缺血后血管生成中的作用仍 largely unknown。在这里，我们发现甲基转移酶样1（METTL1）是导致缺血组织mRNA中m7G整体减少的关键候选因子。METTL1的基因转移改善了血流恢复，并在缺血性损伤后通过增强mRNA的m7G增加了血管生成。使用质粒转染增加METTL1表达促进了人脐静脉内皮细胞（HUVECs）的增殖、迁移和管形成，同时mRNA中的m7G整体增加。机制上，METTL1以m7G甲基化依赖的方式促进血管内皮生长因子A（VEGFA）mRNA的翻译。我们的研究结果强调了mRNA m7G与缺血之间的关键联系，并为在包括外周动脉疾病在内的缺血性疾病的治疗性血管生成中靶向METTL1提供了新的见解。
