Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction  

作　　者：Xiu-xiu Wang Yi-ming Zhao Qian-yun Zhang Jing-xuan Zhao Dao-hong Yin Zi-zhen Zhang Xiao-yan Jin Shuai-nan Li Hao-yu Ji Hong-yang Chen Xiao-fei Guo Yang Yu Wen-ya Ma Hong Yan Han Li Qi-meng Ou-Yang Zhen-wei Pan Hai-hai Liang Ning Wang Wei Chen Ben-zhi Cai Yu Liu 

机构地区：[1]Department of Pharmacy at the Second Affiliated Hospital,and Department of Pharmacology at College of Pharmacy(National Key Laboratory of Frigid Zone Cardiovascular Diseases,Key Laboratory of Cardiovascular Research,Ministry of Education),Harbin Medical University,Harbin,150086,China [2]Institute of Clinical Pharmacology(The Heilongjiang Key Laboratory of Drug Research),Harbin Medical University,Harbin,150086,China [3]Department of Cardiovascular Surgery,The Second Affiliated Hospital of Harbin Medical University,Harbin,150086,China [4]NHC Key Laboratory of Cell Transplantation,The Heilongjiang Key Laboratory of Drug Research,Harbin Medical University,Harbin,150001,China [5]Department of Clinical Laboratory at the Fourth Affiliated Hospital of Harbin Medical University,Harbin,150001,China

出　　处：《Acta Pharmacologica Sinica》2024年第7期1425-1437,共13页中国药理学报（英文版）

基　　金：supported by Heilongjiang Touyan Innovation Team Program [B.Z.C],HMU Marshal Initiative Funding (HMUMIF-21018);the National Natural Science Foundation of China [82272389/92168119/82100300/82000226].

摘　　要：Cardiac fibrosis is a pathological scarring process that impairs cardiac function.N-acetyltransferase 10(Nat10)is recently identified as the key enzyme for the N4-acetylcytidine(ac4C)modification of mRNAs.In this study,we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction(MI)and the related mechanisms.MI was induced in mice by ligation of the left anterior descending coronary artery;cardiac function was assessed with echocardiography.We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI,and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI.Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice.Conversely,fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI.We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing(RIP-seq)in cardiac fibroblasts transfected with Nat10 siRNA,and revealed that angiomotin-like 1(Amotl1),an upstream regulator of the Hippo signaling pathway,was the target gene of Nat10.We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts,thereby increasing the interaction of Amotl1 with yes-associated protein 1(Yap)and facilitating Yap translocation into the nucleus.Intriguingly,silencing of Amotl1 or Yap,as well as treatment with verteporfin,a selective and potent Yap inhibitor,attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro.In conclusion,this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

关 键 词：cardiac fibrosis N-acetyltransferase 10 ac4C-RIP-sequencing Hippo signaling pathway angiomotin-like 1 

分 类 号：R96[医药卫生—药理学]