Study on roles of angiostatic factor IP-10 and Mig in atherogenesis

血管抑制因子IP-10和Mig在动脉粥样硬化形成中的作用研究

• 批准号: 14570665
• 负责人: OCHI Hiroshi
• 金额: $ 1.22万
• 依托单位: Shimane University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570665/
• 关键词: Atherosclerosis; Immunology; IP-10; Mig; I-Tac; ApoE deficient mouse; Ip-10

IFN-inducible protein of 10 kDa (IP-10), IFN-inducible T cell α chemoattractant (I-Tac) and monokine induced by IFN-γ(Mig) are T cell directed CXC chemokines and also anti-angiogenic factors. We investigated roles of IP-10 in intimal neovascularization and atherogenesis in apoE deficient mice fed high cholesterol diet. Intimal neovascularization was evaluated using anti-CD31 Ab and anti-VWF Ab and rarely observed in mice,fed a high cholesterol diet for 30 weeks. We prepared rat anti mouse IP-10 monoclonal antibody (anti-IP-10 mAb) to block the action of IP-10 in apoE deficient mice. Mice were fed a high cholesterol diet from 6 weeks of age and subjected to intra-peritoneal injection of anti-IP-10 mAb (group 1) or PBS (group 2) from 12 weeks to 18 weeks twice a week. Intimal neovascularization was hardly seen in both groups. The mean area of advanced atherosclerotic lesions was similar in both groups. When 6-week-old mice were fed a high cholesterol diet and injected with anti-IP-10 mAb (group 3) or PBS (group 4) for 6 weeks, the mean area of early atherosclerotic lesion of group3 tended to be smaller than that of group 4. These results suggest that IP-10 may play a significant role during the development of early atherosclerotic lesion. However, the number of mice to be studied should be increased to confirm the difference between groups 3 and 4. In addition to animal study, regulation of IP-10, Mig and I-Tac gene expression in cultured endothelial cells was studied. We have reported that a bio-active phospholipid lysophosphatidylcholine (lysoPC) inhibits the interferon (IFN)-γ-induced gene expression of these chemokines in endothelial cells, suggesting immuno-moduratory role of lysoPC. In this project, we elucidated a mechanism responsible for the inhibitory effect of lysoPC : lysoPC inhibits the IFN-γ-induced gene expression of IP-10, Mig and I-Tac at post-transcriptional level

IFN诱导蛋白10（IP-10）、IFN诱导T细胞α趋化因子（I-Tac）和IFN-γ诱导的单核因子（Mig）是T细胞定向的CXC趋化因子，也是抗血管生成因子。我们研究了IP-10在高胆固醇饮食apoE缺陷小鼠内膜新生血管和动脉粥样硬化形成中的作用。使用抗CD 31 Ab和抗VWF Ab评价内膜新生血管形成，在喂食高胆固醇饮食30周的小鼠中很少观察到内膜新生血管形成。我们制备了大鼠抗小鼠IP-10单克隆抗体（anti-IP-10 mAb），以阻断IP-10对apoE基因缺陷小鼠的作用。从6周龄开始给小鼠喂食高胆固醇饮食，并从12周龄至18周龄每周两次腹膜内注射抗IP-10 mAb（组1）或PBS（组2）。内膜新生血管在两组中几乎未见。两组中晚期动脉粥样硬化病变的平均面积相似。当给6周龄小鼠喂食高胆固醇饮食并注射抗IP-10 mAb（组3）或PBS（组4）6周时，组3的早期动脉粥样硬化病变的平均面积倾向于小于组4的平均面积。提示IP-10可能在动脉粥样硬化早期病变的发生发展中起重要作用。但是，应增加研究小鼠的数量，以确认第3组和第4组之间的差异。除了动物研究外，还研究了培养的内皮细胞中IP-10、Mig和I-Tac基因表达的调节。我们已经报道了一种生物活性磷脂溶血磷脂酰胆碱（lysoPC）抑制干扰素（IFN）-γ诱导的内皮细胞中这些趋化因子的基因表达，表明lysoPC的免疫调节作用。本研究阐明了lysoPC抑制IFN-γ诱导的IP-10、Mig和I-Tac基因表达的机制：lysoPC在转录后水平抑制IFN-γ诱导的IP-10、Mig和I-Tac基因表达

项目成果

Ochi H, et al.: "Hyperosmotic stimuli inhibit VCAM-1 expression in cultured endothelial cells via effects on interferon regulatory factor-1 expression and activity"European Journal of Immunology. 32. 1821-1831 (2002)

Ochi H 等人：“高渗刺激通过影响干扰素调节因子-1 表达和活性来抑制培养内皮细胞中的 VCAM-1 表达”《欧洲免疫学杂志》。

Ochi H: "Hyperosmotic stimuli inhibit VCAM-1 expression in cultured endothelial cells via effects on interferon regulatory factor-1 expression and activity."European Journal of Immunology. 32. 1821-1831 (2002)

Ochi H：“高渗刺激通过影响干扰素调节因子-1 表达和活性来抑制培养内皮细胞中的 VCAM-1 表达。”《欧洲免疫学杂志》。

Ochi H: "Hyperrosmotic stimuli inhibit VCAM-1 expression in cultured endothelial cells via effects on interferon regulatory factor-1 expression and activity"European Journal of Immunology. 32. 1821-1831 (2002)

Ochi H：“高渗刺激通过影响干扰素调节因子-1 表达和活性来抑制培养内皮细胞中的 VCAM-1 表达”《欧洲免疫学杂志》。