HUMAN MACROPHAGE-MEDIATED OXIDATION OF LOW-DENSITY-LIPOPROTEIN IS DELAYED AND INDEPENDENT OF SUPEROXIDE PRODUCTION

There is growing evidence that oxidatively modified low-density lipopr otein (LDL) accumulates in the atherosclerotic intima of arteries. Cel ls present in the intima (including the monocyte/macrophage) are capab le of oxidizing LDL in vitro, but the mechanisms by which this occurs are unknown. Several reports have claimed a crucial role for superoxid e as a cell-derived radical species capable of enhancing the rate of L DL oxidation. We have used a sensitive h.p.l.c. system with chemilumin escence detection to measure LDL cholesteryl ester hydroperoxides at e arly stages of LDL oxidation. During the initial stages of LDL oxidati on, there is at least a 2 h delay before human monocyte-derived macrop hages enhance this process. Stimulation of these cells to produce larg e fluxes of superoxide does not increase the rate of LDL oxidation or decrease the delay of its onset. Prior exposure of LDL to a high flux of superoxide does not increase its susceptibility to oxidation by hum an monocyte-derived macrophages. We also show that the thiobarbituric acid-reactive substances (TBARS) assay does not always correlate with more direct methods of assessing LDL oxidation and confirm recent repo rts that superoxide dismutase only partially inhibits cell-mediated LD L oxidation. We conclude that superoxide does not play a major role in human monocyte-derived macrophage-mediated LDL oxidation under the co nditions that we describe.