Free radicals and low-density lipoprotein oxidation by macrophages

The concentration-dependent effects of a series of lipoxygenase inhibitors and antioxidants on the macrophage-mediated oxidative modification of low-density lipoprotein (LDL) were measured. Their influence on macrophage 5-lipoxygenase pathway activity was also studied over the same concentration range. No correlation between inhibition of 5-lipoxygenase and of macrophage-mediated oxidation of LDL was observed. The capacity of the compounds to prevent cell-mediated modification of LDL could be explained in terms of their activity as either aqueous- or lipid-peroxyl radical scavengers. Two potent 5-lipoxygenase inhibitors (MK 886 and Revlon 5901), which had no radical-scavenging properties, were unable to block LDL modification. It is concluded that 5-lipoxygenase is not essential for LDL oxidation by macrophages.

Section: Discussionsupporting

confidence: 53%

5-Lipoxygenase is not essential in macrophage-mediated oxidation of low-density lipoprotein

Jessup

Darley‐Usmar

O'leary

et al. 1991

“…However, neither 02nor H202 cause lipid peroxidation unless ions of such transition metals as iron or copper are present, to catalyse their conversion into morereactive radical species such as hydroxyl (OH') (reviewed in [12]). Indeed, transition-metal ions are probably required for all these cell-dependent oxidations of LDL [13,14], and copper ions are frequently used in vitro to obtain peroxidized LDL recognizable by the macrophage scavenger receptors [3,[15][16][17][18][19]. Iron and copper ions capable of catalysing free-radical reactions such as lipid peroxidation do not exist in plasma from healthy human subjects [20][21][22][23]: these metals are safely bound to such proteins as transferrin and ferritin (iron) or caeruloplasmin and albumin (copper) [12,23].…”

Section: Methodsmentioning

confidence: 99%

“…Iron and copper ions capable of catalysing free-radical reactions such as lipid peroxidation do not exist in plasma from healthy human subjects [20][21][22][23]: these metals are safely bound to such proteins as transferrin and ferritin (iron) or caeruloplasmin and albumin (copper) [12,23]. If the studies described above [13][14][15][16][17][18][19] are indeed relevant to the situation in vivo, then 'catalytic' iron and copper ions should exist within atherosclerotic lesions. We therefore attempted to demonstrate this directly.…”

Section: Methodsmentioning

confidence: 99%

Stimulation of lipid peroxidation and hydroxyl-radical generation by the contents of human atherosclerotic lesions

Smith

Mitchinson

Aruoma

et al. 1992

419

167

Lipid peroxidation within human arterial lesions is thought to play an important role in the development of atherosclerosis. Peroxidation can be accelerated by the presence of 'catalytic' iron or copper ions. Gruel samples from advanced atherosclerotic lesions in the abdominal aortae of human cadavers were tested for pro-oxidant properties. All samples contained bleomycin-detectable iron and phenanthroline-detectable copper. Almost all gruel samples stimulated peroxidation of rat liver microsomes, and this was usually inhibited by the iron-ion chelator desferrioxamine. Some samples stimulated formation of hydroxyl radicals from H2O2 in the presence of ascorbate, a reaction again inhibited by desferrioxamine. We conclude that the interior of human advanced atherosclerotic lesions is a highly pro-oxidant environment, and that the use of copper or iron ions to promote peroxidation of low-density lipoproteins in vitro may be a valid model for events in the arterial wall.

“…This process would rely on transfer of these plasma-membrane lipids to the LDL particle or release of lipoxygenase to the extracellular environment, where it could utilize LDL lipid as substrate. However, a number of groups have presented evidence which disagrees with these mechanisms [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Human macrophage-mediated oxidation of low-density lipoprotein is delayed and independent of superoxide production

Garner

Dean

Jessup

1994

There is growing evidence that oxidatively modified low-density lipoprotein (LDL) accumulates in the atherosclerotic intima of arteries. Cells present in the intima (including the monocyte/macrophage) are capable of oxidizing LDL in vitro, but the mechanisms by which this occurs are unknown. Several reports have claimed a crucial role for superoxide as a cell-derived radical species capable of enhancing the rate of LDL oxidation. We have used a sensitive h.p.l.c. system with chemiluminescence detection to measure LDL cholesteryl ester hydroperoxides at early stages of LDL oxidation. During the initial stages of LDL oxidation, there is at least a 2 h delay before human monocyte-derived macrophages enhance this process. Stimulation of these cells to produce large 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 human 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 reports that superoxide dismutase only partially inhibits cell-mediated LDL oxidation. We conclude that superoxide does not play a major role in human monocyte-derived macrophage-mediated LDL oxidation under the conditions that we describe.