Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis
Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis
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LncRNA NORAD 下调促进 Ox-LDL 诱导的血管内皮细胞损伤和动脉粥样硬化
DOI：
10.18632/aging.103034
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发表时间：
2020-04-15
期刊：
影响因子：
5.2
通讯作者：
Zhang, Chunxiang
中科院分区：
文献类型：
--
作者：
Bian, Weihua;Jing, Xiaohong;Zhang, Chunxiang
长链非编码RNA（lncRNA）在血管疾病的发生发展中起着重要作用。然而，lncRNA NORAD对动脉粥样硬化的影响仍然未知。本研究旨在探讨NORAD对内皮细胞损伤和动脉粥样硬化的影响。Ox-LDL处理的人脐静脉内皮细胞（HUVEC）和高脂饮食（HFD）喂养的ApoE（-/-）小鼠用作体外和体内模型。结果显示，NORAD基因敲低可使细胞周期阻滞于GO/G1期，加重ox-LDL诱导的细胞存活率下降、细胞凋亡和细胞衰老，并沿着Bax、P53、P21和切割型caspase-3的表达增加，Bcl-2的表达减少。通过NORAD过表达进一步验证NORAD对细胞活力的影响。NORAD基因敲低可增加ox-LDL诱导的活性氧、丙二醛、p-IKB α表达水平和NF-κ B核转位。NORAD-敲低也增加了促炎分子ICAM、VCAM和IL-8.此外，我们确定了NORAD和IL-8转录抑制因子SFPQ在HUVECs中的强相互作用。在ApoE（-/-）小鼠中，NORAD敲低增加了脂质紊乱和动脉粥样硬化病变。结果提示，ncRNANORAD通过NF-κ B和p53-p21信号通路以及IL-8抑制内皮细胞衰老、内皮细胞凋亡和动脉粥样硬化，其中NORAD对IL-8的作用可能是通过与SFPQ的直接相互作用实现的。
Long noncoding RNAs (lncRNAs) play important roles in the development of vascular diseases. However, the effect of lncRNA NORAD on atherosclerosis remains unknown. This study aimed to investigate the effect NORAD on endothelial cell injury and atherosclerosis. Ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and high-fat-diet (HFD)-fed ApoE(-/-) mice were used as in vitro and in vivo models. Results showed that NORAD-knockdown induced cell cycle arrest in GO/G1 phase, aggravated ox-LDL-induced cell viability reduction, cell apoptosis, and cell senescence along with the increased expression of Bax, P53, P21 and cleaved caspase-3 and the decreased expression of Bcl-2. The effect of NORAD on cell viability was further verified via NORAD-overexpression. NORAD- knockdown increased ox-LDL-induced reactive oxygen species, malondialdehyde, p-IKB alpha expression levels and NF-kappa B nuclear translocation. Proinflammatory molecules ICAM, VCAM, and IL-8 were also increased by NORAD- knockdown. Additionally, we identified the strong interaction of NORAD and IL-8 transcription repressor SFPQ in HUVECs. In ApoE(-/- )mice, NORAD-knockdown increased the lipid disorder and atherosclerotic lesions. The results have suggested that lncRNA NORAD attenuates endothelial cell senescence, endothelial cell apoptosis, and atherosclerosis via NF-kappa B and p53-p21 signaling pathways and IL-8, in which NORAD-mediated effect on IL-8 might through the direct interaction with SFPQ.