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

Xiu-xiu Wang1,2, Yi-ming Zhao1,2, Qian-yun Zhang1,2, Jing-xuan Zhao1,2, Dao-hong Yin1,2, Zi-zhen Zhang1,2, Xiao-yan Jin1, Shuai-nan Li1, Hao-yu Ji1,2, Hong-yang Chen1,2, Xiao-fei Guo1,2, Yang Yu1,2, Wen-ya Ma1,2, Hong Yan1, Han Li1,2, Qi-meng Ou-Yang1,2, Zhen-wei Pan1, Hai-hai Liang1, Ning Wang1, Wei Chen3, Ben-zhi Cai1,2,4, Yu Liu5
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
Correspondence to: Ning Wang:, Wei Chen:, Ben-zhi Cai:, Yu Liu:,
DOI: 10.1038/s41401-024-01306-8
Received: 8 January 2024
Accepted: 6 May 2024
Advance online: 5 June 2024


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.
Keywords: cardiac fibrosis; N-acetyltransferase 10; ac4C-RIP-sequencing; Hippo signaling pathway; angiomotin-like 1

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