CircARCN1 通过调节巨噬细胞中由 HuR 介导的 USP31 mRNA 而加重动脉粥样硬化。

IF 10.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Zhicheng Pan, Jialan Lv, Liding Zhao, Kaidi Xing, Runze Ye, Yuesheng Zhang, Siyuan Chen, Peng Yang, Hailong Yu, Yangkai Lin, Ruobing Li, Dongfei Wang, Juan Fang, Yang Dong, Jianpeng Sheng, Xiaolin Wang, Ge Shan, Shan Zhang, Hongqiang Cheng, Qingbo Xu, Xiaogang Guo
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引用次数: 0

摘要

目的:环状 RNA(circRNA)被认为是生物过程的重要调节因子,但它们对动脉粥样硬化发展(冠状动脉疾病(CAD)的关键因素)的影响尚未完全阐明。我们的目的是研究它们在 CAD 患者中的潜在用途以及动脉粥样硬化的发病机制:我们选择了稳定型心绞痛(SA)或急性冠状动脉综合征(ACS)患者和对照组进行转录组学筛选,并对血细胞中的 circRNAs 进行量化。我们对颈动脉斑块样本进行了 circRNAs 染色,并在体外进行了功能增益和功能缺失研究。我们采用了 Western 印迹、蛋白质相互作用分析和分子方法来进行机理研究。在腺相关病毒介导的基因干预功能研究中采用了载脂蛋白E-/-小鼠模型。我们发现,在 SA 或 ACS 患者的外周血单核细胞中,特别是在 ACS 患者的外周血单核细胞中,circARCN1 表达升高。此外,较高的 circARCN1 水平与罹患 SA 和 ACS 的较高风险相关。我们还观察到颈动脉斑块中 circARCN1 的表达升高。进一步分析表明,circARCN1 主要在单核细胞和巨噬细胞中表达,这在动脉粥样硬化斑块中也得到了证实。我们的体外研究提供了证据,证明 circARCN1 影响了 HuR 与泛素特异性肽酶 31(USP31)mRNA 之间的相互作用,导致 USP31 介导的 NF-κB 激活减弱。有趣的是,当用腺相关病毒敲除载脂蛋白E-/-小鼠巨噬细胞中的circARCN1时,动脉粥样硬化斑块中的巨噬细胞积聚和炎症明显减少,而在该模型中circARCN1的过表达则会加重动脉粥样硬化病变:我们的研究结果提供了确凿的证据,表明巨噬细胞表达的 circARCN1 通过调节 HuR 介导的 USP31 mRNA 稳定性和 NF-κB 激活,在动脉粥样硬化的发展过程中发挥作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CircARCN1 aggravates atherosclerosis by regulating HuR-mediated USP31 mRNA in macrophages.

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.

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来源期刊
Cardiovascular Research
Cardiovascular Research 医学-心血管系统
CiteScore
21.50
自引率
3.70%
发文量
547
审稿时长
1 months
期刊介绍: Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases
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