Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells
Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells
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DOI：
10.1074/jbc.m104812200
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发表时间：
2001-12-07
影响因子：
4.8
通讯作者：
Owen, JS
中科院分区：
文献类型：
--
作者：
Stannard, AK;Riddell, DR;Owen, JS
单核细胞的内皮下浸润发生在动脉粥样硬化的早期，并由激活的内皮上上调的细胞黏附分子促进。载脂蛋白E(ApoE)有助于防止动脉粥样硬化，部分原因是巨噬细胞分泌的apoE颗粒在病变部位具有局部有益作用。在这里，我们假设这种保护包括抗炎作用，并研究细胞来源的载脂蛋白E是否可以抑制肿瘤坏死因子-a介导的血管细胞黏附分子-1(VCAM-1)在人脐静脉内皮细胞(HuVECs)中的上调。两个模型被用来模拟内皮细胞对巨噬细胞来源的载脂蛋白E的暴露。首先，瞬时转染人脐静脉内皮细胞分泌载脂蛋白E；血管细胞黏附分子-1诱导量与载脂蛋白E分泌呈负相关(r=-0.76，p<；0.001)。在第二个实验中，表达载脂蛋白E的重组中国仓鼠卵巢(CHO)细胞培养液与人脐静脉内皮细胞孵育后，血管细胞黏附分子-1的表达也呈剂量依赖性降低(r=-0.70，p<；0.001)。CHO(ApoE)细胞来源的apoE的特征表明，它与人血单核细胞来源的巨噬细胞分泌的apoE颗粒有几个相似之处。载脂蛋白E抑制内皮细胞激活很可能是通过刺激内皮型一氧化氮合酶来实现的；载脂蛋白E增加了细胞内一氧化氮及其替代标志物环鸟苷一磷酸的水平，而一氧化氮合酶抑制剂乙基异硫脲则阻断了它的作用。我们认为，巨噬细胞在病变部位局部分泌的载脂蛋白E可能通过刺激内皮细胞释放NO和抑制VCAM-1的表达而发挥抗炎作用。
Sub-endothelial infiltration of monocytes occurs early in atherogenesis and is facilitated by cell adhesion molecules that are up-regulated on activated endothelium. Apolipoprotein E (apoE) helps protect against atherosclerosis, in part, because apoE particles secreted by macrophages have local beneficial effects at lesion sites. Here, we hypothesize that such protection includes antiinflammatory actions and investigate whether cell-derived apoE can inhibit tumor necrosis factor-a-mediated up-regulation of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HuVECs). Two models were used to mimic endothelial exposure to macrophage-derived apoE. In the first, HUVECs were transiently transfected to secrete apoE; VCAM-1 induction inversely correlated with secretion of apoE into the media (r = -0.76, p < 0.001). In the second, incubation of HUVECs with media from recombinant Chinese hamster ovary (CHO) cells expressing apoE (CHO(apoE)) also reduced VCAM-1 in a dose-dependent manner (r = -0.70, p < 0.001). Characterization of CHO(apoE) cell-derived apoE revealed several similarities to apoE particles secreted by human blood monocyte-derived macrophages. The suppression of endothelial activation by apoE most likely occurs via stimulation of endothelial nitric oxide synthase; apoE increased levels of intracellular nitric oxide and its surrogate marker, cyclic guanosine monophosphate, while the nitric oxide synthase inhibitor, ethyl-isothiourea, blocked its effect. We propose that apoE secreted locally at lesion sites by macrophages may be anti-inflammatory by stimulating endothelium to release NO and suppress VCAM-1 expression.