ICAM-1-related noncoding RNA accelerates atherosclerosis by amplifying NF-κB signaling.

Journal of molecular and cellular cardiology 2022 Sep

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Long noncoding RNAs (lncRNAs) are critical regulators of inflammation with great potential as new therapeutic targets. However, the role of lncRNAs in early atherosclerosis remains poorly characterized. This study aimed to identify the key lncRNA players in activated endothelial cells (ECs). The lncRNAs in response to pro-inflammatory factors in ECs were screened through RNA sequencing. ICAM-1-related non-coding RNA (ICR) was identified as the most potential candidate for early atherosclerosis. ICR is essential for intercellular adhesion molecule-1 (ICAM1) expression, EC adhesion and migration. In a high fat diet-induced atherosclerosis model in mice, ICR is upregulated in the development of atherosclerosis. After intravenous injection of adenovirus carrying shRNA for mouse ICR, the atherosclerotic plaque area was markedly reduced with the declined expression of ICR and ICAM1. Mechanistically, ICR stabilized the mRNA of ICAM1 in quiescent ECs; while under inflammatory stress, ICR upregulated ICAM1 in a nuclear factor kappa B (NF-κB) dependent manner. RNA-seq analysis showed pro-inflammatory targets of NF-κB were regulated by ICR. Furthermore, the chromatin immunoprecipitation assays showed that p65 binds to ICR promoter and facilitates its transcription. Interestingly, ICR, in turn, promotes p65 accumulation and activity, forming a positive feedback loop to amplify NF-κB signaling. Preventing the degradation of p65 using proteasome inhibitors rescued the expression of NF-κB targets suppressed by ICR. Taken together, ICR acts as an accelerator to amplify NF-κB signaling in activated ECs and suppressing ICR is a promising early intervention for atherosclerosis through ICR/p65 loop blockade. Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Citation

Shuangjin Ding, Jiankun Liu, XiaoRui Han, Wanqiu Ding, Zhirui Liu, Ying Zhu, Wenxing Zhan, Yiqi Wan, Shujie Gai, Junjie Hou, Xiaoxia Wang, Yixia Wu, Andong Wu, Chuan-Yun Li, Zhe Zheng, Xiao-Li Tian, Huiqing Cao. ICAM-1-related noncoding RNA accelerates atherosclerosis by amplifying NF-κB signaling. Journal of molecular and cellular cardiology. 2022 Sep;170:75-86