哈尔滨医科大学Yu Liu等研究人员合作发现，N-乙酰转移酶10对Amotl1的乙酰胞嘧啶修饰有助于心肌梗死后小鼠心脏纤维化扩张。相关论文于2024年6月5日在线发表于国际学术期刊《中国药理学报》。

研究人员探讨了N-乙酰转移酶10（Nat10）在心肌梗死（MI）后心脏纤维化中的作用及其相关机制。通过结扎左前降支冠状动脉诱发小鼠心肌梗死，并用超声心动图评估心功能。研究人员发现，心肌梗死后4周，Nat10在梗死区和边界区的mRNA和蛋白表达水平均显著升高，心肌梗死后，Nat10在心脏成纤维细胞中的表达明显高于在心肌细胞中的表达。成纤维细胞特异性过表达Nat10可促进胶原蛋白沉积，诱发小鼠心肌梗死后心脏收缩功能障碍。相反，成纤维细胞特异性敲除Nat10能明显缓解心肌梗死后的心脏功能损伤和细胞外基质重塑。

随后，研究人员在转染了Nat10 siRNA的心成纤维细胞中进行了N4-乙酰胞嘧啶（ac4C）-RNA结合蛋白免疫沉淀测序（RIP-sequq），结果发现，Hippo信号通路的上游调控因子Angiomotin-like 1（Amotl1）是Nat10的靶基因。研究人员证实，Nat10介导的对Amotl1的ac4C修饰增加了其在新生心脏成纤维细胞中的mRNA稳定性和翻译，从而增加了Amotl1与yes相关蛋白1（Yap）的相互作用，促进了Yap向细胞核的转位。

耐人寻味的是，沉默Amotl1或Yap，以及用选择性强效Yap抑制剂verteporfin处理，可减轻Nat10过表达诱导的心成纤维细胞增殖，并阻止其体外分化为肌成纤维细胞。总之，该研究强调了Nat10是心肌梗死损伤后心肌纤维化的一个关键调节因子，它通过ac4C修饰Hippo/Yap信号通路中的上游激活因子。

据介绍，心脏纤维化是一种损害心脏功能的病理瘢痕形成过程。Nat10最近被确认为对mRNA进行ac4C修饰的关键酶。

附：英文原文

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

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

Issue&Volume: 2024-06-05

Abstract: 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.

DOI: 10.1038/s41401-024-01306-8

Source: https://www.nature.com/articles/s41401-024-01306-8