DIRECT COPPER REDUCTION BY MACROPHAGES - ITS ROLE IN LOW-DENSITY-LIPOPROTEIN OXIDATION

Oxidation of low density lipoprotein (LDL) results in changes to the l ipoprotein that are potentially atherogenic. Numerous studies have sho wn that macrophages cultured in vitro can promote LDL oxidation via a transition metal-dependent process, yet the exact mechanisms that are responsible for macrophage-mediated LDL oxidation are not understood, One contributing mechanism may be the ability of macrophages to reduce transition metals. Reduced metals (such as Fe(II) or Cu(I)) rapidly r eact with lipid hydroperoxides, leading to the formation of reactive l ipid radicals and conversion of the reduced metal to its oxidized form . We demonstrate here the ability of macrophages to reduce extracellul ar iron and copper and identify a contributing mechanism, Evidence is provided that a proportion of cell-mediated metal reduction is due to direct transplasma membrane electron transport, Glucagon suppressed bo th macrophage-mediated metal reduction and LDL oxidation, Although met al reduction was augmented when cells were provided with a substrate f or thiol production, thiol export was not a strict requirement for cel l-mediated metal reduction, Similarly, while the metal-dependent accel eration of LDL oxidation by macrophages was augmented by thiol product ion, macrophages could still promote LDL oxidation when thiol export w as minimized (by substrate limitation). This study identifies a novel mechanism that may contribute to macrophage-mediated LDL oxidation and may also reveal potential new strategies for the inhibition of this p rocess.