Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein

Rosenblat, M.; Belinky, P.; Vaya, J.; Levy, R.; Hayek, T.; Coleman, R.; Merchav, S.; Aviram, M.

Journal of Biological Chemistry 274(20): 13790-13799

1999


ISSN/ISBN: 0021-9258
Accession: 003194209

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Abstract
In vitro studies, using mouse peritoneal macrophages (MPMs) and the J-774 A.1 macrophage-like cell line were performed. Both cells accumulated up to 1.5 micro g of glabridin/mg of cell protein after 2 h of incubation, and this process was time- and glabridin dose-dependent. In parallel, in glabridin-enriched cells, macrophage-mediated oxidation of LDL was inhibited by up to 80% in comparison with control cells. Glabridin inhibited superoxide release from MPMs in response to phorbol 12-myristate 13-acetate, or to LDL when added together with copper ions, by up to 60%. Translocation of P-47, a cytosolic component of NADPH oxidase to the plasma membrane was substantially inhibited. In glabridin-enriched macrophages, protein kinase C activity reduced by ~70%. All of the above effects of glabridin required the presence of the two hydroxyl groups on the flavonoids B phenol ring. In order to assess the physiological significance of these results, we next performed in vivo studies, using the atherosclerotic apolipoprotein E-deficient (E degrees ) mice. MPMs harvested from glabridin-treated E degrees mice (20 micro g/mouse daily for a period of 6 weeks) demonstrated reduced capability to oxidize LDL by 80% in comparison with placebo-treated mice. This latter phenomenon was associated with a reduction in the lesion oxysterols and a 50% reduction in the aortic lesion size. It is concluded that glabridin accumulation in macrophages is associated with reduced cell-mediated oxidation of LDL and decreased activation of the NADPH oxidase system. These phenomena could be responsible for the attenuation of atherosclerosis in E degrees mice, induced by glabridin.