Investigation of the functional molecules and mechanism on the LDL oxidation causing atherosclerosis -essential roles of 12/15-lipoxygenase-

LDL氧化导致动脉粥样硬化的功能分子和机制研究-12/15-脂氧合酶的重要作用-

• 批准号: 14570101
• 负责人: TAKAHASHI Yoshitaka
• 金额: $ 2.24万
• 依托单位: KANAZAWA 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-14570101/
• 关键词: 12; 15-Lipoxygenase; Macrophage; Oxidized LDL; LDL-receptor-related protein; Cholesteryl ester; 15-リポシゲナーゼ; トランスロケーション

Oxidative modification of LDL is a critical step for the development of atherosclerosis. 12/15-Lipoxygenase highly expressed in macrophages is proposed to play a key role of the LDL oxidation ; however, the mechanism on the oxidation of extracellular LDL by intracellular enzyme was not known. We found that binding of LDL to the LDL-receptor-related protein(LRP), a cell-surface receptor expressed in macrophages, is required for the 12/15-lipoxygenase-mediates LDL oxidation by macrophages. The binding of the LDL to the LRP was found to translocates the cytosolic 12/15-lipoxygenase to the plasma membrane in macrophages and the transloation was required for the LDL oxidation. Furthermore, the cholesteryl ester in the LDL particle was selectively transferred to the plasma membrane of macrophages after binding of LRP. These results strongly suggest that cholesteryl ester in LDL is oxygenated in the plasma membrane by membrane-associated 12/15-lipoxygenase, transferred back to the LDL particle, and sequential radical chain reaction generates the oxidized LDL which is recognized by scavenger receptor in macrophages leading to the foam cell formation. These findings would be useful for the development of the medicines for this 'common disease with a novel mechanism.

LDL的氧化修饰是动脉粥样硬化发展的关键步骤。巨噬细胞中高表达的12/15-脂氧合酶被认为在LDL氧化过程中起关键作用，但细胞内酶氧化细胞外LDL的机制尚不清楚。我们发现LDL与LDL受体相关蛋白（LRP）（巨噬细胞中表达的细胞表面受体）的结合是12/15-脂氧合酶介导的LDL被巨噬细胞氧化所必需的。发现LDL与LRP的结合使巨噬细胞中的胞质12/15-脂氧合酶易位至质膜，并且该易位是LDL氧化所需的。此外，胆固醇酯在LDL颗粒选择性转移到细胞膜的LRP结合后的巨噬细胞。这些结果强烈地表明，LDL中的胆固醇酯在质膜中被膜相关的12/15-脂氧合酶氧化，转移回LDL颗粒，并且连续的自由基链反应产生氧化的LDL，其被巨噬细胞中的清道夫受体识别，导致泡沫细胞形成。这些发现将有助于开发治疗这种具有新机制的常见疾病的药物。

项目成果

Zhu, H., Y.Takahaahi, W.Xu, H.Kawajiri, T.Murakami, et al.: "Low density lipoprotein receptor-related protein-mediated membrane translocation of 12/15-lipoxygenase is required for oxidation of low density lipoprotein by macrophages"Journal of Biological C

Zhu, H., Y.Takahaahi, W.Xu, H.Kawajiri, T.Murakami, et al.：“低密度脂蛋白受体相关蛋白介导的 12/15-脂氧合酶膜易位是低密度脂蛋白氧化所必需的。

Yoshimoto, T, Y.Takahashi: "Arachidonate 12-lipoxygenases"Prostaglandins and Other Lipid Mediators. 68. 245-262 (2002)

Yoshimoto，T，Y.Takahashi：“花生四烯酸 12-脂氧合酶”前列腺素和其他脂质介质。

Takahashi, Y., T.Yoshimoto: "What are the functions of mammalian 8-, 12-, and 15-lipoxygenases?"Research Advances in Cancer. 2. 221-229 (2002)

Takahashi, Y., T.Yoshimoto：“哺乳动物 8-、12- 和 15-脂氧合酶的功能是什么？”癌症研究进展。

Xu, W., Y.Takahashi, T.Sakashita, T.Iwasaki, H.Hattori, T.Yoshimoto: "Low density lipoprotein receptor-related protein is required for macrophage-mediated oxidation of low density lipoprotein by 12/15-lipoxygenase."J Biol Chem.. 276. 36454-36459 (2001)

Xu, W., Y.Takahashi, T.Sakashita, T.Iwasaki, H.Hattori, T.Yoshimoto：“低密度脂蛋白受体相关蛋白是巨噬细胞介导的 12/15-脂氧合酶氧化低密度脂蛋白所必需的

Fujita, H., K.Koshida, E.T.Keller, Y.Takahashi, T.Yoshimoto et al.: "Cyclooxygenase-2 promotes prostate cancer progression"Prostate. 53. 232-240 (2002)

Fujita, H., K.Koshida, E.T.Keller, Y.Takahashi, T.Yoshimoto 等人：“Cyclooxygenase-2 促进前列腺癌进展”前列腺。