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

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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.