OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization
OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization
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OX40配体通过血管新生血管形成在动脉粥样硬化的发展中发挥重要作用
DOI：
10.1093/cvr/cvq211
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Shimokawa H.
中科院分区：
文献类型：
--
作者：
Nakano M;Fukumoto Y;Satoh K;Ito Y;Kagaya Y;Ishii N;Sugamura K;Shimokawa H.
目的动脉粥样硬化以炎性细胞浸润和血管形成增加为特征，可能与免疫学机制有关。OX40是肿瘤坏死因子受体超家族的膜结合分子，由活化的T细胞表达，而OX40配体(OX40L)则表达于活化的巨噬细胞和内皮细胞。方法和结果高脂饮食饲养8周的载脂蛋白E缺陷(ApoE−/−)小鼠和ApoE−/−/OX40L双缺陷(ApoE−/−/OX40L−/−)小鼠。载脂蛋白E−/−/OX40L−/−小鼠的动脉粥样硬化程度明显低于载脂蛋白E−/−小鼠。我们还用或不用MGP34抗体(OX40L特异性中和抗体)处理高脂喂养的−/−小鼠10周。治疗后，与对照组相比，MGP34治疗组小鼠的动脉粥样硬化程度再次显著减少。重要的是，与载脂蛋白E−/−/OX40L−/−小鼠相比，ApoE−/−小鼠的主动脉外膜血管密度和血管内皮生长因子诱导的Matrigel分析活体血管生成显著减少。结论血管OX40/OX40L系统在血管形成及随后的动脉粥样硬化形成中起重要作用，提示血管OX40/OX40L系统可能成为动脉粥样硬化治疗的新靶点。
AimsAtherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis.Methods and resultsWe examined apolipoprotein E-deficient (ApoE−/−) mice and ApoE−/−/OX40L-double-deficient (ApoE−/−/OX40L−/−) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE−/−/OX40L−/−mice compared with ApoE−/−mice. We also treated high-fat-fed ApoE−/−mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assayin vivowere significantly reduced in ApoE−/−/OX40L−/−mice compared with ApoE−/−mice. Finally, when high-fat-fed ApoE−/−mice were transplanted with bone marrow cells from either wild-type or OX40L−/−mice, the extent of aortic atheroma was comparable between the two groups.ConclusionThese results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.