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

Abstract

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.

Transition metal ions within human atherosclerotic lesions can catalyse the oxidation of low density lipoprotein by macrophages

“…As expected, Chelex-100 removed either copper or iron ions that had been added to Ham's F-10 medium and prevented them from catalysing LDL oxidation. These observations are supported by the work of Smith et al [17] and Swain and Gutteridge [18], who showed that gruel from atherosclerotic lesions contained significant levels of catalytically active copper and iron ions that were able to catalyse the oxidation of rat liver microsomes or linoleic acid micelles.…”

“…It has been demonstrated by Smith et al [17], however, that gruel extracted from advanced atherosclerotic lesions from human aortas can contain significant amounts of catalytically active copper (0-28 /IM) or iron ions (0-7/IM). This finding has very recently been *Corresponding author.…”

The effect of heparin on Cu2+‐mediated oxidation of human low‐density lipoproteins

“…This model of oxidation was demonstrated to produce LDL sharing many structural and functional properties with LDL oxidized by cells [15] or extracted from atherosclerotic plaques [16]. Moreover, it should be reminded that Cu 2÷ ions are contained in aortic wall and increase in atherosclerotic plaques [3], where they may contribute to the development of the lesion by oxidative stress. On this basis, we suggest that HE (and probably other glycosaminoglycans occurring in native PGs) might play a regulatory role in the process of LDL oxidation in vivo, which may change the metabolic fate of the particle, increasing its atherogenic potential [1,2].…”

“…Samples of LDL corresponding to 80/.tg cholesterol/ml were then oxidized with 0.9, 1.8 and 3.6/zM CuSO4. These concentrations are in the range originally used by Gieseg and Esterbauer [10] and in the same order of magnitude as those described in atherosclerotic plaques [3]. The oxidation was performed in PBS at 30°C, in the absence and in the presence of HE (varying from 150 to 750/lg/ml, corresponding to 72 362/~g/ml of hexuronate) (Sigma).…”

“…Moreover, atherosclerotic arterial wall contains increased levels of copper and iron ions, which induce LDL oxidation [3]. In this compartment, LDL may interact also with proteoglycans (PGs), forming complexes that are taken up avidly by macrophages [4,5].…”