CircARCN1 aggravates atherosclerosis by regulating HuR-mediated USP31 mRNA in macrophages

• Published in: Cardiovascular research Vol. 120; no. 13; pp. 1531 - 1549
• Main Authors: Pan, Zhicheng, Lv, Jialan, Zhao, Liding, Xing, Kaidi, Ye, Runze, Zhang, Yuesheng, Chen, Siyuan, Yang, Peng, Yu, Hailong, Lin, Yangkai, Li, Ruobing, Wang, Dongfei, Fang, Juan, Dong, Yang, Sheng, Jianpeng, Wang, Xiaolin, Shan, Ge, Zhang, Shan, Cheng, Hongqiang, Xu, Qingbo, Guo, Xiaogang
• Format: Journal Article
• Language: English
• Published: UK Oxford University Press 05-11-2024
• Subjects: Inflammation; circRNA; circARCN1; Macrophages; Atherosclerosis
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvae148

Abstract
Aims
Circular RNAs (circRNAs) are considered important regulators of biological processes, but their impact on atherosclerosis development, a key factor in coronary artery disease (CAD), has not been fully elucidated. We aimed to investigate their potential use in patients with CAD and the pathogenesis of atherosclerosis.
Methods and results
Patients with stable angina (SA) or acute coronary syndrome (ACS) and controls were selected for transcriptomic screening and quantification of circRNAs in blood cells. We stained carotid plaque samples for circRNAs and performed gain- and loss-of-function studies in vitro. Western blots, protein interaction analysis, and molecular approaches were used to perform the mechanistic study. ApoE−/− mouse models were employed in functional studies with adeno-associated virus-mediated genetic intervention. We demonstrated elevated circARCN1 expression in peripheral blood mononuclear cells from patients with SA or ACS, especially in those with ACS. Furthermore, higher circARCN1 levels were associated with a higher risk of developing SA and ACS. We also observed elevated expression of circARCN1 in carotid artery plaques. Further analysis indicated that circARCN1 was mainly expressed in monocytes and macrophages, which was also confirmed in atherosclerotic plaques. Our in vitro studies provided evidence that circARCN1 affected the interaction between HuR and ubiquitin-specific peptidase 31 (USP31) mRNA, resulting in attenuated USP31-mediated NF-κB activation. Interestingly, macrophage accumulation and inflammation in atherosclerotic plaques were markedly decreased when circARCN1 was knocked down with adeno-associated virus in macrophages of ApoE−/− mice, while circARCN1 overexpression in the model exacerbated atherosclerotic lesions.
Conclusions
Our findings provide solid evidence macrophagic-expressed circARCN1 plays a role in atherosclerosis development by regulating HuR-mediated USP31 mRNA stability and NF-κB activation, suggesting that circARCN1 may serve as a factor for atherosclerotic lesion formation.
Graphical Abstract
Graphical Abstract
CircARCN1 promoted the macrophage inflammatory response and atherosclerotic lesion development. It functions by affecting the interaction between HuR and USP31 mRNA, and down-regulated USP31, thus attenuating the inhibitory effect of USP31 on NF-κB activation, resulting in activated macrophage inflammation.