scholarly journals Reduction of Cu(II) by lipid hydroperoxides: implications for the copper-dependent oxidation of low-density lipoprotein

1997 ◽  
Vol 322 (2) ◽  
pp. 425-433 ◽  
Author(s):  
Rakesh P. PATEL ◽  
Dimitri SVISTUNENKO ◽  
Michael T. WILSON ◽  
Victor M. DARLEY-USMAR
Keyword(s):  
Lipid Peroxidation ◽  
Amino Acid ◽  
Unsaturated Fatty Acids ◽  
Low Density Lipoprotein ◽  
Biological Significance ◽  
Density Lipoprotein ◽  
Peroxyl Radicals ◽  
Lipid Hydroperoxides ◽  
Low Density ◽  
Amino Acid Residues

The Cu(II)-promoted oxidation of lipids is a lipid hydroperoxide (LOOH)-dependent process that has been used routinely to assess the oxidizability of low-density lipoprotein (LDL) in human subjects. Metal-dependent redox reactions, including those mediated by copper, have been implicated in the pathogenesis of atherosclerosis. Despite its widespread use and possible biological significance, key elements of the mechanism are not clear. For example, although it is evident that copper acts as a catalyst, which implies a redox cycle between the Cu(II) and Cu(I) redox states, the reductants remain uncertain. In LDL these could include α-tocopherol, amino acid residues on the protein and LOOH. However, both α-tocopherol and amino acid residues are probably consumed before the most rapid phase of lipid peroxidation occurs, suggesting that another reductant must be donating electrons to Cu(II), the most likely candidate being LOOH. This role has been disputed, since LDLs nominally devoid of LOOH are still capable of reducing Cu(II) to Cu(I) and thermodynamic calculations for this reaction are not favourable. Direct investigation of the role of LOOH as reductant has not been reported and in the present study, using simple lipid systems and LDL, we have re-examined this issue using the Cu(I) chelator bathocuproine. We have shown that Cu(II) may promote lipid peroxidation in liposomes, which do not contain either protein or α-tocopherol, and that this is associated with reduction to Cu(I). The data also indicate that an equilibrium between free Cu(II) and LOOH exists, which only in the presence of an oxidizable substrate, i.e. unsaturated fatty acids, is shifted towards formation of Cu(I) and lipid-derived peroxyl radicals. We propose that reduction of Cu(II) by LOOH is a necessary component in sustaining the propagation of lipid peroxidation and that the formation of peroxyl radicals and their products in a lipid environment is sufficient to overcome thermodynamic barriers to the reaction.

scholarly journals Resistance of lipoprotein(a) to lipid peroxidation induced by oxygenated free radicals produced by γ radiolysis: a comparison with low-density lipoprotein

1996 ◽  
Vol 314 (1) ◽  
pp. 277-284 ◽  
Author(s):  
Jean-Louis BEAUDEUX ◽  
Monique GARDES-ALBERT ◽  
Jacques DELATTRE ◽  
Alain LEGRAND ◽  
François ROUSSELET ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Free Radicals ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peroxyl Radicals ◽  
Low Density ◽  
Lipoprotein A ◽  
Acetylneuraminic Acid ◽  
Paired Samples ◽  
Apolipoprotein A

Lipid peroxidation of lipoprotein(a) [Lp(a)] by defined oxygen-centred free radicals (O2-· /OH·, O2-·, O2-· /HO2·) produced by γ radiolysis was compared with that of paired samples of low-density lipoprotein (LDL). Lp(a) appeared to be more resistant to oxidation than LDL, as indicated by the kinetic study of four markers of lipid peroxidation: decrease in vitamin E, formation of conjugated dienes and aldehydic products, and modification of electrophoretic mobility. In contrast, similar kinetics of lipid peroxidation were obtained for LDL and Lp(a-), which is the lipoparticle issued following the reductive cleavage of apolipoprotein(a) from Lp(a), thus suggesting that the greater resistance of Lp(a) to lipid peroxidation was due to the presence of apolipoprotein(a). Lipid peroxidation of Lp(a) and LDL induced by peroxyl radicals, which were produced by an azo compound [2,2′-azobis-(2-amidinopropane)dihydrochloride], confirmed both the resistance of Lp(a) to lipid peroxidation and the propensity of Lp(a-) to exhibit a greater susceptibility to oxidation than intact Lp(a). Our findings also indicated that the high content of apolipoprotein(a) in N-acetylneuraminic acid residues was only partly responsible for the resistance of Lp(a) to oxidation.

scholarly journals Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant

1992 ◽  
Vol 288 (2) ◽  
pp. 341-344 ◽  
Author(s):  
V W Bowry ◽  
K U Ingold ◽  
R Stocker
Keyword(s):  
Lipid Peroxidation ◽  
Vitamin E ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peroxyl Radicals ◽  
Careful Examination ◽  
Early Event ◽  
Low Density ◽  
Tocopheroxyl Radical

Uptake of oxidatively modified low-density lipoprotein (LDL) by cells in the arterial wall is believed to be an important early event in the development of atherosclerosis. Because vitamin E is the major antioxidant present in human lipoproteins, it has received much attention as a suppressor of LDL lipid oxidation and as an epidemiological marker for ischaemic heart disease. However, a careful examination of lipid peroxidation in LDL induced by a steady flux of aqueous peroxyl radicals has demonstrated that, following consumption of endogenous ubiquinol-10, the rate of peroxidation (i) declines as vitamin E is consumed, (ii) is faster in the presence of vitamin E than following its complete consumption, (iii) is substantially accelerated by enrichment of the vitamin in LDL, either in vitro or by diet, and (iv) is virtually independent of the applied radical flux. We propose that perodixation is propagated within lipoprotein particles by reaction of the vitamin E radical (i.e. alpha-tocopheroxyl radical) with polyunsaturated fatty acid moieties in the lipid. This lipid peroxidation mechanism, which can readily be rationalized by the known chemistry of the alpha-tocopheroxyl radical and by the radical-isolating properties of fine emulsions such as LDL, explains how reagents which reduce the alpha-tocopheroxyl radical (i.e. vitamin C and ubiquinol-10) strongly inhibit lipid peroxidation in vitamin E-containing LDL.

scholarly journals Detection of new epitopes formed upon oxidation of low-density lipoprotein, lipoprotein (a) and very-low-density lipoprotein. Use of an antiserum against 4-hydroxynonenal-modified low-density lipoprotein

1990 ◽  
Vol 265 (2) ◽  
pp. 605-608 ◽  
Author(s):  
G Jürgens ◽  
A Ashy ◽  
H Esterbauer
Keyword(s):  
Unsaturated Fatty Acids ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Lipid Hydroperoxides ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Dependent Manner ◽  
Lipoprotein A

4-Hydroxynonenal (HNE) is a major aldehydic propagation product formed during peroxidation of unsaturated fatty acids. The aldehyde was used to modify freshly prepared human low-density lipoprotein (LDL). A polyclonal antiserum was raised in the rabbit and absorbed with freshly prepared LDL. The antiserum did not react with human LDL, but reacted with CuCl2-oxidized LDL and in a dose-dependent manner with LDL, modified with 1, 2 and 3 mM-HNE, in the double-diffusion analysis. LDL treated with 4 mM of hexanal or hepta-2,4-dienal or 4-hydroxyhexenal or malonaldehyde (4 or 20 mM) did not react with the antiserum. However, LDL modified with 4 mM-4-hydroxyoctenal showed a very weak reaction. Lipoprotein (a) and very-low-density lipoprotein were revealed for the first time to undergo oxidative modification initiated by CuCl2. This was evidenced by the generation of lipid hydroperoxides and thiobarbituric acid-reactive substances, as well as by a marked increase in the electrophoretic mobility. After oxidation these two lipoproteins also reacted positively with the antiserum against HNE-modified LDL.

scholarly journals Oxidation of low-density lipoprotein by hypochlorite causes aggregation that is mediated by modification of lysine residues rather than lipid oxidation

1994 ◽  
Vol 302 (1) ◽  
pp. 297-304 ◽  
Author(s):  
L J Hazell ◽  
J J M van den Berg ◽  
R Stocker
Keyword(s):  
Lipid Peroxidation ◽  
Lipid Oxidation ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Size Exclusion ◽  
Lipid Hydroperoxides ◽  
Low Density ◽  
Lysine Residues

Peroxidation of low-density lipoprotein (LDL) lipid is generally thought to represent the initial step in a series of modification reactions that ultimately transform the protein moiety of the lipoprotein into a form recognized by receptors different from those that bind native LDL. Uptake of LDL via these alternative receptors can lead to the formation of lipid-laden cells, which are typical for the early stages of atherogenesis. We have studied the oxidative modification of LDL by hypochlorite (-OCl), a powerful oxidant produced from H2O2 and chloride via the action of myeloperoxidase which is released from activated neutrophils and monocytes. Exposure of LDL to reagent or enzymically generated -OCl at 4 or 37 degrees C resulted in immediate and preferential oxidation of amino acid residues of apolipoprotein B-100, the single protein associated with LDL. Lysine residues quantitatively represented the major target and, like tryptophan, were oxidized to approximately the same extent with reagent or enzymically generated -OCl. In contrast, LDL lipid oxidation was less favoured than protein oxidation, as judged by the amounts of lipid hydroperoxides, chlorohydrins, cholesterol or fatty acid oxidation products formed. Treatment with -OCl caused aggregation of LDL, as shown by an increased turbidity of the oxidized LDL solution and elution from a size-exclusion h.p.l.c. column of high-molecular-mass LDL complexes. Chemical modification of lysine residues before oxidation with -OCl prevented aggregation, while it enhanced the extent of lipid peroxidation. Treatment of LDL with -OCl also caused the formation of carbonyl groups and release of ammonia; both these modifications were inhibited by lysine-residue modification before oxidation. These results demonstrate that aggregation reactions are dependent on initial lysine oxidation by -OCl, followed by deamination and carbonyl formation, but do not involve lipid (per)oxidation. We propose that the observed -OCl-mediated aggregation of LDL is caused, at least in part, by cross-linking of apoproteins by Schiff-base formation independently of lipid peroxidation.

Oxidative Modification of Low-Density Lipoprotein and Atherogenetic Risk in β-Thalassemia

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3936-3942 ◽  
Author(s):  
M.A. Livrea ◽  
L. Tesoriere ◽  
A. Maggio ◽  
D. D’Arpa ◽  
A.M. Pintaudi ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Vitamin E ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Lipid Hydroperoxides ◽  
Low Density ◽  
Healthy Controls ◽  
The Mean ◽  
Β Carotene

We investigated the oxidative state of low-density lipoprotein (LDL) in patients with β-thalassemia to determine whether there was an association with atherogenesis. Conjugated diene lipid hydroperoxides (CD) and the level of major lipid antioxidants in LDL, as well as modified LDL protein, were evaluated in 35 β-thalassemia intermedia patients, aged 10 to 60, and compared with age-matched healthy controls. Vitamin E and β-carotene levels in LDL from patients were 45% and 24% of that observed in healthy controls, respectively. In contrast, the mean amount of LDL-CD was threefold higher and lysil residues of apo B-100 were decreased by 17%. LDL-CD in thalassemia patients showed a strong inverse correlation with LDL vitamin E (r = −0.784; P < .0001), while a negative trend was observed with LDL-β–carotene (r = −0.443; P = .149). In the plasma of thalassemia patients, malondialdehyde (MDA), a byproduct of lipid peroxidation, was increased by about twofold, while vitamin E showed a 52% decrease versus healthy controls. LDL-CD were inversely correlated with plasma vitamin E (r = −0.659; P < .0001) and correlated positively with plasma MDA (r = 0.621; P < .0001). Plasma ferritin was positively correlated with LDL-CD (r = 0.583; P =.0002). No correlation was found between the age of the patients and plasma MDA or LDL-CD. The LDL from thalassemia patients was cytotoxic to cultured human fibroblasts and cytotoxicity increased with the content of lipid peroxidation products. Clinical evidence of mild to severe vascular complications in nine of the patients was then matched with levels of LDL-CD, which were 36% to 118% higher than the mean levels of the patients. Our results could account for the incidence of atherogenic vascular diseases often reported in β-thalassemia patients. We suggest that the level of plasma MDA in β-thalassemia patients may represent a sensitive index of the oxidative status of LDL in vivo and of its potential atherogenicity.

Oxidative Modification of Low-Density Lipoprotein and Atherogenetic Risk in β-Thalassemia

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3936-3942 ◽  
Author(s):  
M.A. Livrea ◽  
L. Tesoriere ◽  
A. Maggio ◽  
D. D’Arpa ◽  
A.M. Pintaudi ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Vitamin E ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Lipid Hydroperoxides ◽  
Low Density ◽  
Healthy Controls ◽  
The Mean ◽  
Β Carotene

Abstract We investigated the oxidative state of low-density lipoprotein (LDL) in patients with β-thalassemia to determine whether there was an association with atherogenesis. Conjugated diene lipid hydroperoxides (CD) and the level of major lipid antioxidants in LDL, as well as modified LDL protein, were evaluated in 35 β-thalassemia intermedia patients, aged 10 to 60, and compared with age-matched healthy controls. Vitamin E and β-carotene levels in LDL from patients were 45% and 24% of that observed in healthy controls, respectively. In contrast, the mean amount of LDL-CD was threefold higher and lysil residues of apo B-100 were decreased by 17%. LDL-CD in thalassemia patients showed a strong inverse correlation with LDL vitamin E (r = −0.784; P &lt; .0001), while a negative trend was observed with LDL-β–carotene (r = −0.443; P = .149). In the plasma of thalassemia patients, malondialdehyde (MDA), a byproduct of lipid peroxidation, was increased by about twofold, while vitamin E showed a 52% decrease versus healthy controls. LDL-CD were inversely correlated with plasma vitamin E (r = −0.659; P &lt; .0001) and correlated positively with plasma MDA (r = 0.621; P &lt; .0001). Plasma ferritin was positively correlated with LDL-CD (r = 0.583; P =.0002). No correlation was found between the age of the patients and plasma MDA or LDL-CD. The LDL from thalassemia patients was cytotoxic to cultured human fibroblasts and cytotoxicity increased with the content of lipid peroxidation products. Clinical evidence of mild to severe vascular complications in nine of the patients was then matched with levels of LDL-CD, which were 36% to 118% higher than the mean levels of the patients. Our results could account for the incidence of atherogenic vascular diseases often reported in β-thalassemia patients. We suggest that the level of plasma MDA in β-thalassemia patients may represent a sensitive index of the oxidative status of LDL in vivo and of its potential atherogenicity.

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