NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation
NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation
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DOI：
10.1016/j.yjmcc.2014.12.015
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发表时间：
2015-03-01
影响因子：
5
通讯作者：
Martinez-Gonzalez, Jose
中科院分区：
文献类型：
--
作者：
Calvayrac, Olivier;Rodriguez-Calvo, Ricardo;Martinez-Gonzalez, Jose
最近的工作强调了NR 4A受体在动脉粥样硬化和炎症中的作用。然而，在血管平滑肌细胞（VSMC）增殖中，NOR-1（神经元衍生孤儿受体-1）对Nur 77和Nur 1发挥拮抗作用。本研究的目的是分析NOR-1在VSMC炎症反应中的作用。我们评估了这种受体的功能获得对VSMC对炎症刺激的反应的后果。在人VSMC中，NOR-1的慢病毒过表达减少了脂多糖（LPS）诱导的细胞因子（IL-1 β、IL-6和IL-8）和趋化因子（MCP-1和CCL 20）的上调。在用TNF α或oxLDL刺激的细胞中获得了类似的效果。相反，siRNA介导的NOR-1抑制显著增加促炎介质的表达。有趣的是，在来自VSMC中过表达人NOR-1的转基因小鼠（TgNOR-1）中，LPS对细胞因子/趋化因子的上调低于野生型同窝仔。在转基因动物的VSMC中获得了类似的结果。NOR-1降低了NF κ B敏感启动子的转录活性（在瞬时转染中），以及NF κ B与其响应元件的结合（在电泳迁移率变动测定中）。此外，NOR-1通过降低I κ B α磷酸化/降解和抑制磷酸化以及随后的p65向核的移位来防止NF κ B通路的激活（通过Western印迹和免疫细胞化学评估）。这些作用与ERK 1/2、p38 MAPK和Jun N-末端激酶的磷酸化减弱有关，这些途径参与NF κ B的活化。在用LPS攻击的小鼠中，在主动脉中来自TgNOR-1的NF κ B信号传导的活化也减弱。我们的数据支持NOR-1作为血管系统中促炎刺激引起的急性反应的负调节剂的作用。(C)2014爱思唯尔有限公司版权所有。
Recent work has highlighted the role of NR4A receptors in atherosclerosis and inflammation. In vascular smooth muscle cell (VSMC) proliferation, however, NOR-1 (neuron-derived orphan receptor-1) exerts antagonistic effects to Nur77 and Nurr1. The aim of this study was to analyse the effect of NOR-1 in VSMC inflammatory response. We assessed the consequence of a gain-of-function of this receptor on the response of VSMC to inflammatory stimuli. In human VSMC, lentiviral over-expression of NOR-1 reduced lipopolysaccharide (LPS)-induced up-regulation of cytokines (IL-1 beta, IL-6 and IL-8) and chemokines (MCP-1 and CCL20). Similar effects were obtained in cells stimulated with TNF alpha or oxLDL Conversely, siRNA-mediated NOR-1 inhibition significantly increased the expression of pro-inflammatory mediators. Interestingly, in the aortas from transgenic mice that over-express human NOR-1 in VSMC (TgNOR-1), the up-regulation of cytokine/chemokine by LPS was lower compared to wild-type littermates. Similar results were obtained in VSMC from transgenic animals. NOR-1 reduced the transcriptional activity of NF kappa B sensitive promoters (in transient transfections), and the binding of NF kappa B to its responsive element (in electrophoretic mobility shift assays). Furthermore, NOR-1 prevented the activation of NF kappa B pathway by decreasing I kappa B alpha phosphorylation/degradation and inhibiting the phosphorylation and subsequent translocation of p65 to the nucleus (assessed by Western blot and immunocytochemistry). These effects were associated with an attenuated phosphorylation of ERK1/2, p38 MAPK and Jun N-terminal kinase, pathways involved in the activation of NF kappa B. In mouse challenged with LPS, the activation of the NF kappa B signalling was also attenuated in the aorta from TgNOR-1. Our data support a role for NOR-1 as a negative modulator of the acute response elicited by pro-inflammatory stimuli in the vasculature. (C) 2014 Elsevier Ltd. All rights reserved.