NDRG2 induced by oxidized LDL in macrophages antagonizes growth factor productions via selectively inhibiting ERK activation
NDRG2 induced by oxidized LDL in macrophages antagonizes growth factor productions via selectively inhibiting ERK activation
复制标题
巨噬细胞中氧化 LDL 诱导的 NDRG2 通过选择性抑制 ERK 激活来拮抗生长因子的产生。
DOI：
10.1016/j.bbalip.2009.09.022
复制
发表时间：
2010-02-01
影响因子：
4.8
通讯作者：
Rui, Yao-Cheng
中科院分区：
文献类型：
--
作者：
Liu, Shumei;Yang, Pengyuan;Rui, Yao-Cheng
在动脉粥样硬化形成过程中，巨噬细胞泡沫细胞产生大量的生长因子、细胞因子和趋化因子，在动脉粥样硬化斑块形成的炎症过程中发挥核心作用。在本研究中，我们发现了一个新的蛋白质标记物，N-Myc下游调节蛋白2(NDRG2)，它在氧化低密度脂蛋白(OxLDL)处理的巨噬细胞和人类动脉粥样硬化斑块中显著上调。过表达和siRNA敲除研究表明，NDRG2是巨噬细胞产生血小板衍生生长因子(PDGF)和血管内皮生长因子(VEGF)的负调控因子。此外，我们还研究了NDRG2对MAPK信号激活的影响。我们的结果表明，NDRG2对血管内皮生长因子和血小板衍生生长因子产生的调节是由ERK1/2激活起作用，而不是P38或JNK1/2激活。与PDGF水平一致的是，血管平滑肌细胞(VSMC)的增殖也受到含有NDRG2基因敲除或过表达的oxLDL处理的巨噬细胞条件培养液的调节。中和抗PDGF抗体可显著抑制NDRG2基因敲除的巨噬细胞培养上清液促进的VSMC增殖。我们的研究结果表明，NDRG2参与oxLDL诱导的巨噬细胞活化，并调节依赖ERK1/2的PDGF和VEGF的产生，这在动脉粥样硬化的发生中具有潜在的应用价值。(C)2009爱思唯尔B.V.保留所有权利。
During atherogenesis, macrophage foam cells produce prodigious growth factors, cytokines, and chemokines, which play the central roles in inflammatory process in atherosclerotic plaque formation. In the present study, we identified a new protein marker, N-Myc downstream-regulated protein 2 (NDRG2), which is significantly up-regulated in oxidized low density lipoprotein (oxLDL) treated macrophages and in human atherosclerotic plaques. Over-expression and siRNA knockdown studies showed that NDRG2 is a negative regulator of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) productions in macrophages. Furthermore, we investigated the effects of NDRG2 on MAPK signal activation. Our results showed ERK1/2 activation, but not P38 or JNK1/2 activation, is responsible for regulation of NDRG2 on VEGF and PDGF productions. Consistent with the PDGF levels, the vascular smooth muscle cell (VSMC) proliferation was also regulated by the conditional medium of the oxLDL treated macrophages with NDRG2 knockdown or over-expression. Neutralizing anti-PDGF antibody can significantly inhibit the enhanced VSMC proliferation by macrophage medium with NDRG2 knockdown. Our present results demonstrate that NDRG2 participates in oxLDL-induced macrophage activation and modulates ERK1/2-dependent PDGF and VEGF production, which has potential application in atherogenesis. (C) 2009 Elsevier B.V. All rights reserved.