新型长非编码 lncARF 通过抑制泡沫细胞的自噬作用介导高同型半胱氨酸血症诱发动脉粥样硬化

Ning Ding, Shengchao Ma, Qingning Chang, Lin Xie, Guizhong Li, Yinju Hao, Jiantuan Xiong, Anning Yang, Xiaoling Yang, Yideng Jiang, Huiping Zhang
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引用次数: 0

摘要

简介同型半胱氨酸(Hcy)是公认的动脉粥样硬化的独立危险因素。长非编码 RNA(lncRNA)是包括动脉粥样硬化在内的病理生理过程的新兴调节因子,但其参与 Hcy 诱导的动脉粥样硬化的潜在机制在很大程度上仍然未知:本研究的主要目的是评估lncARF(Hcy诱导的自噬相关因子)在Hcy诱导的动脉粥样硬化中的作用及相关机制:方法:对经 Hcy 处理的泡沫细胞进行 RNA 测序,发现了一种名为 lncARF 的新型特异性长非编码 RNA。锁定核酸gapmeRs介导的lncARF敲除被用于探索lncARF在体内和体外的作用。质谱分析、RNA牵引和RNA免疫沉淀(RIP)试验被用来揭示lncARF的机理作用。质谱分析和染色质免疫沉淀(ChIP)被用来检测转录因子介导的lncARF的转录激活。在临床上,利用接收者操作特征曲线(ROC)分析评估了lncARF在高同型半胱氨酸血症(HHcy)动脉粥样硬化患者中的诊断价值:我们观察到lncARF在动脉粥样硬化斑块中的表达大幅上调,敲除lncARF可促进泡沫细胞的自噬,从而减少动脉粥样硬化病变的形成。从机理上讲,lncARF与RRAGD物理结合并抑制其泛素化,从而进一步激活PI3K/Akt和MAPK信号通路。此外,体外实验表明,转录因子FosB可抑制DNMT1与lncARF启动子的结合,从而通过DNA低甲基化激活转录。在临床上,lncARF的表达与血清Hcy水平呈正相关,它能以较高的ROC曲线下面积、灵敏度和特异性区分HHcy动脉粥样硬化患者:我们的研究强调了lncARF保护动脉粥样硬化发展的机制,涉及表观遗传修饰、RRAGD/PI3K/Akt和RRAGD/MAPK信号通路,这可能为改善动脉粥样硬化治疗提供新的诊断生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Novel long noncoding lncARF mediated hyperhomocysteinemia-induced atherosclerosis via autophagy inhibition in foam cells.

Introduction: Homocysteine (Hcy) is well recognized to be an independent risk factor for atherosclerosis. Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis, while the underlying mechanisms of its involvement in Hcy induced-atherosclerosis remain largely unknown.

Objectives: The primary aim of this study is to assess the role of lncARF (autophagy-related factor induced by Hcy) in Hcy induced-atherosclerosis and related mechanism.

Methods: RNA sequencing of foam cells treated with Hcy revealed a novel specific long noncoding RNA called lncARF. Locked nucleic acid gapmeRs-mediated lncARF knockdown was used to explore the role of lncARF both in vivo and in vitro. Mass spectrometry, RNA pull-down and RNA immunoprecipitation (RIP) assays were employed to uncover a mechanistic role of lncARF. Mass array assay and chromatin immunoprecipitation (ChIP) were used to detect the transcriptional activation of lncARF mediated by transcription factor. Clinically, receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic value of lncARF in atherosclerotic patients with hyperhomocysteinemia (HHcy).

Results: We observed that the expression of lncARF was substantially upregulated in atherosclerotic plaques, and knockdown of lncARF decreased the formation of atherosclerotic lesions by promoting autophagy in foam cells. Mechanistically, lncARF physically binds to RRAGD and inhibits its ubiquitination, further activating the PI3K/Akt and MAPK signaling pathways. Moreover, in vitro experiments showed that transcription factor FosB inhibited the binding of DNMT1 at the lncARF promoter, leading to transcriptional activation through DNA hypomethylation. Clinically, lncARF expression was positively correlated with serum Hcy levels, and it could distinguish atherosclerotic patients with HHcy with a high area under the ROC curve, sensitivity and specificity.

Conclusions: Our study highlights the mechanisms of lncARF in protecting against the development of atherosclerosis involving the epigenetic modifications and RRAGD/PI3K/Akt and RRAGD/MAPK signaling pathways, which may provide novel diagnostic biomarkers to improve atherosclerosis treatment.

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