Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation,Journal of Advanced Research

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Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2020-07-31 , DOI: 10.1016/j.jare.2020.07.015
Pengcheng Li ₁ , Junhui Xing ₁ , Jielei Zhang ₂ , Jianwu Jiang ₃ , Xuemeng Liu ₁ , Di Zhao ₂ , Yanzhou Zhang ₁

Affiliation

Introduction

In atherosclerotic lesions, extensive inflammation of the vessel wall contributes to plaque instability. Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes in atherosclerosis.

Objectives

Here, we aim to identify the functional role and regulatory mechanisms of lncRNA hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) in atherosclerotic inflammation.

Methods

An atherosclerotic mouse model was induced in ApoE-/- mice by high fat diet (HFD). Endothelial cells (ECs), human aortic smooth muscle cells (SMCs) or human coronary artery endothelial cells (HCAECs) were exposed to ox-LDL to develop the in vitro model. The effects of lncRNA HIF1A-AS2 on inflammation were evaluated by determining levels of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) and levels of adhesion molecules vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and macrophage cationic peptide 1 (MCP-1).

Results

It was established that lncRNA HIF1A-AS2 and ATF2 were highly expressed in atherosclerotic ApoE-/- mice. Downregulating lncRNA HIF1A-AS2 in ox-LDL-exposed ECs, SMCs and HCAECs inhibited inflammation by reducing levels of pro-inflammatory factors and adhesion molecules. LncRNA HIF1A-AS2 bound to the transcription factor USF1 to elevate ATF2 expression. USF1 overexpression counteracted the suppressive effect of lncRNA HIF1A-AS2 silencing on ox-LDL-induced inflammation. Knockdown of lncRNA HIF1A-AS2 or ATF2 could also attenuate inflammation in atherosclerotic mice. Collectively, the present study demonstrates that downregulation of lncRNA HIF1A-AS2 represses the binding of USF1 to the ATF2 promoter region and then inhibits ATF2 expression, thereby suppressing atherosclerotic inflammation.

Conclusion

This study suggests lncRNA HIF1A-AS2 as an promising therapeutic target for atherosclerosis.

中文翻译：

抑制长链非编码 RNA HIF1A-AS2 通过 ATF2 下调提供对动脉粥样硬化的保护

介绍

在动脉粥样硬化病变中，血管壁的广泛炎症导致斑块不稳定。长链非编码 RNA (lncRNA) 在动脉粥样硬化的多种生物学过程中发挥着重要作用。

目标

在这里，我们旨在确定 lncRNA 缺氧诱导因子 1 α-反义 RNA 2 (HIF1A-AS2) 在动脉粥样硬化炎症中的功能作用和调控机制。

方法

通过高脂饮食 (HFD) 在 ApoE-/- 小鼠中诱导动脉粥样硬化小鼠模型。将内皮细胞 (ECs)、人主动脉平滑肌细胞 (SMCs) 或人冠状动脉内皮细胞 (HCAECs) 暴露于 ox-LDL 以开发体外模型。通过测定炎症因子肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素6（IL-6）的水平以及粘附分子的水平来评估lncRNA HIF1A-AS2对炎症的影响血管细胞粘附分子 1 (VCAM-1)、细胞间粘附分子 1 (ICAM-1) 和巨噬细胞阳离子肽 1 (MCP-1)。

结果

确定 lncRNA HIF1A-AS2 和 ATF2 在动脉粥样硬化 ApoE-/- 小鼠中高表达。在 ox-LDL 暴露的 EC、SMC 和 HCAEC 中下调 lncRNA HIF1A-AS2 通过降低促炎因子和粘附分子的水平来抑制炎症。LncRNA HIF1A-AS2 与转录因子 USF1 结合以提高 ATF2 的表达。USF1 过表达抵消了 lncRNA HIF1A-AS2 沉默对 ox-LDL 诱导的炎症的抑制作用。敲除 lncRNA HIF1A-AS2 或 ATF2 也可以减轻动脉粥样硬化小鼠的炎症。总之，本研究表明lncRNA HIF1A-AS2的下调抑制了USF1与ATF2启动子区域的结合，然后抑制了ATF2的表达，从而抑制了动脉粥样硬化炎症。