Mettl1 knockdown alleviates cardiac I/R injury in mice by inactivating the Mettl1-CYLD-P53 positive feedback loop  

作　　者：Shu-ting Yu Zhi-yong Sun Na Li Zhe-zhe Qu Chang-hao Wang Tian-tian Ju Ying-qi Liu Zhong-ting Mei Kui-wu Liu Mei-xi Lu Min Huang Ying Li Shun-kang Dou Jian-hao Jiang Yao-zhi Zhang Chuan-hao Huang Xiao-chen Pang Ying-qiong Jia Xian-hui Dong Fan Wu Yi Zhang Wan-hong Li Bao-feng Yang Wei-jie Du 

机构地区：[1]Department of Pharmacology(The State-Province Key Laboratories of Biomedicine Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin,150081,China [2]National Key Laboratory for Innovation and Transformation of Luobing Theory,The Key Laboratory of Cardiovascular Remodeling and Function Research,Chinese Ministry of Education,Chinese National Health Commission and Chinese Academy of Medical Sciences,Department of Cardiology,Qilu Hospital of Shandong University,Jinan,250012,China [3]Traditional Chinese Medicine School,Beijing University of Chinese Medicine,Beijing,102488,China [4]State Key Laboratory of Frigid Zone Cardiovascular Diseases(SKLFZCD),Department of Pharmacology(State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin,150081,China [5]Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070),Chinese Academy of Medical Sciences,Harbin,150081,China [6]Northern Translational Medicine Research and Cooperation Center,Heilongjiang Academy of Medical Sciences,Harbin Medical University,Harbin,150081,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期592-605,共14页中国药理学报(英文版)

基　　金：supported by grants from the National Natural Science Foundation of China(82273928,82473919,82330011,U21A20339);Natural Science Foundation for Distinguished Young Scholars of Heilongjiang Province(2024JQ0107);Youth Project of Scientific Research Institution of Heilongjiang Province(CZKYF2023-1-C047);CAMS Innovation Fund for Medical Sciences(CIFMS,2020-I2M-5-003).

摘　　要：The N7-methylguanosine(m7G)methyltransferase Mettl1 has been recently implicated in cardiac repair and fibrosis.In this study we investigated the role of Mettl1 in mouse cardiomyocytes injury and the underlying mechanisms.Cardiac ischemia/reperfusion(I/R)I/R model was established in mice by ligation of the left anterior descending coronary artery(LAD)for 45 min followed by reperfusion for 24 h.We showed the mRNA and protein levels of Mettl1 were significantly upregulated in mouse I/R hearts and H2O2-treated neonatal mouse cardiomyocytes(NMCMs).Mettl1 knockdown markedly ameliorated cardiac I/R injury,evidenced by decreased infarct size,apoptosis,and improved cardiac function.Overexpression of Mettl1 triggered cardiomyocytes apoptosis in vivo and in vitro.By performing RNA sequencing combined with m7G methylated RNA sequencing in Mettl1-overexpressing mouse hearts,we revealed that Mettl1 catalyzed m7G modification of the deubiquitinase cylindromatosis(CYLD)mRNA to increase the expression of CYLD,which enhanced the stability of P53 via abrogating its ubiquitination degradation.Vice versa,P53 served as a transcriptional factor to positively regulate Mettl1 expression during I/R injury.Knockdown of CYLD mitigated cardiomyocytes apoptosis induced by Mettl1 overexpression or oxidative stress.From the available drug-targets databases and literature,we identified 4 small molecule inhibitors of m7G modification.Sinefungin,one of the Mettl1 inhibitors exerted profound protection against cardiac I/R injury in vivo and in vitro.Collectively,this study has identified Mettl1 as a key regulator of cardiomyocyte apoptosis,and targeting the Mettl1-CYLD-P53 positive feedback circuit may represent a novel therapeutic avenue for alleviating cardiac I/R injury.

关 键 词：cardiac ischemia/reperfusion injury Mettl1 m7G CYLD P53 UBIQUITINATION 

分 类 号：R54[医药卫生—心血管疾病]