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

低密度脂蛋白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氧化中起关键作用；然而，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）的结合是巨噬细胞中表达的一种细胞表面受体，12/15-脂氧合酶介导LDL被巨噬细胞氧化所必需的。在巨噬细胞中，LDL与LRP的结合可将细胞质12/15-脂氧合酶转移到质膜上，而这种转移是LDL氧化所必需的。此外，LDL颗粒中的胆固醇酯与LRP结合后选择性转移到巨噬细胞的质膜上。这些结果强烈提示，LDL中的胆固醇酯在质膜中被膜相关的12/15脂氧合酶氧化，并转移回LDL颗粒，随后自由基链反应生成氧化LDL，并被巨噬细胞清道夫受体识别，从而形成泡沫细胞。这些发现将有助于开发具有新机制的治疗这种“常见病”的药物。

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.