The role of lipid peroxidation and antioxidants in oxidative modification of LDL

Esterbauer, Hermann; Gebicki, Janusz M.; Puhl, Herbert; Jürgens, Günther

doi:10.1016/0891-5849(92)90181-f

Cited by 2,146 publications

(1,281 citation statements)

References 246 publications

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“…Several data support the hypothesis that the early phase of the oxLDL-induced EGFR activation is mediated (at least in part) by 4-HNE (Suc et al, 1998) and is an antioxidantinsensitive event: (i) free (chemically active) 4-HNE is present in oxLDL (beside the 4-HNE-adducts to apoB or lipids) (Esterbauer et al, 1987) or may be continuously formed by decomposition of polyunsaturated fatty acid hydroperoxides (Esterbauer et al, 1992); (ii) both the oxLDL-induced EGFR derivatization and activation are mimicked by incubation of cultured cells with exogenous 4-HNE; (iii) in vitro, 4-HNE Figure 6 Ca eic acid and tyrphostin A46 (but not trolox) inhibit EGF-induced EGFR activation (inhibition of the EGFR tyrosine kinase). (A) B82LK+ cells, pre-incubated for 1 h with or without ca eic acid (100 mM), trolox (100 mM) or tyrphostin A46 (20 mM) before treatment with EGF (2 nM for 20 min) (Co, untreated control).…”

Section: Discussionmentioning

confidence: 81%

“…Antioxidants, from dietary (such as ca eic acid or tocopherol) or synthetic (such as trolox or PDTC) origin, may prevent at least in part this e ect of oxLDL, either by preventing LDL oxidation (Esterbauer et al, 1992) or by acting at the cellular level by reducing the oxidative stress triggered by oxLDL (this study). But it is to note that antioxidants were unable to prevent the part of oxLDL-induced EGFR activation mediated by 4-HNE.…”

Section: Discussionmentioning

confidence: 91%

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Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

Vacaresse

Vieira

Robbesyn

et al. 2001

British J Pharmacology

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1 Oxidized low density lipoproteins (oxLDL) are thought to play a major role in atherosclerosis. OxLDL act in part through alteration of intracellular signalling pathways in cells of the vascular wall. We recently reported that the EGF receptor (EGFR) signalling pathway is activated by lipid peroxidation products (among them 4-hydroxynonenal, 4-HNE) contained in oxLDL. 2 The use of phenolic antioxidants, such as trolox, alpha-tocopherol, ca eic acid and tyrphostins A-25, A-46 or A-1478, showed that the oxLDL-induced EGFR activation is constituted by two separate components, the ®rst (early) one being antioxidant-insensitive, the second (late) being antioxidant-sensitive. 3 4-HNE derivatization of EGFR and EGFR activation induced by exogenous 4-HNE, suggest that the early (0.5 ± 3 h) component of oxLDL-induced EGFR activation is mediated (at least in part) by 4-HNE (and possibly by other oxidized lipids). This early component is antioxidantinsensitive. 4 The second component (4 ± 5 h) of the oxLDL-induced EGFR activation is antioxidant-sensitive, since it is blocked by antioxidants such as trolox, ca eic acid or PDTC, which act by blocking the cellular oxidative stress (H 2 O 2 generation) evoked by oxLDL. Conversely, exogenous H 2 O 2 induced EGFR autophosphorylation (thus mimicking the second component) and was also inhibited by antioxidants. This e ect is mediated in part through inhibition by oxidative stress of protein tyrosine phosphatases involved in EGFR dephosphorylation.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 91%

Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

Vacaresse

Vieira

Robbesyn

et al. 2001

British J Pharmacology

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“…as insulin resistance increases there is simultaneous increase in oxidative stress and vice versa (Figure 1 ). Since oxidative stress is due to the imbalance between protective antioxidants and damaging free radicals (20), subjects with metabolic syndrome were found to have significantly low levels of antioxidant vitamins as compared to other groups (Table 3) 9 The decreased concentration of antioxidant vitamins in metabolic syndrome may be attributed to lower intake of fruits & vegetables rich in antioxidants or increased use of antioxidants to counteract oxidative stress (21) 9 However, no significant difference in antioxidant status, oxidative stress and insulin resistance could be made out in first-degree non-diabetic subjects and spouses with metabolic syndrome indicating that CHD risk due to prevailing contributory dsk factor remains the same in those with or without genetic predisposition.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress in metabolic syndrome

Sharma

Mishra

Ajmera

et al. 2005

Indian J Clin Biochem

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As antioxidants play a protective role in the pathophysiology of diabetes and cardiovascular diseases, understanding the physiological status of antioxidant concentration among people at high risk for developing these conditions, such as Metabolic Syndrome, is of interest. In present study out of 187 first degree non-diabetic relatives and 192 non-diabetic spouses, 33.1% and 19.7 % were found to have metabolic syndrome respectively. Subjects with metabolic syndrome (> 3 risk factors) had poor antioxidants status as reflected by significantly low levels of vitamin A, C & E and significantly increased (p < 0.01) oxidative stress as compared to those without metabolic syndrome. At the same time serum insulin levels and insulin resistance were found to be significantly high (p < 0.001) in metabolic syndrome. A strong positive correlation (r=0.946; p<0.001) between oxidative stress and insulin resistance was observed in metabolic syndrome. Low levels of antioxidants and increased oxidative stress with insulin resistance in metabolic syndrome suggests that besides therapeutic life style changes (TLC) as suggested in ATP III guidelines inclusion of antioxidant vitamins, fruits and vegetable could be beneficial to ward off the consequences of metabolic syndrome.

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“…Although it is questionable that the compounds used in this study are present in vivo, the structural requirements of a good substrate for the enzymes seem to be compatible with the anti-oxidative scavenger role of both enzymes. It seems reasonable for an enzyme to possess broad substrate specificity toward lipidic esters if it serves a protective role against oxidative stress since oxidative damage occurs not only from phospholipids but also from various types of compounds containing unsaturated bonds through uncontrolled free radical reactions (2). The brain enzymes, PAF-AH(Ib) R1/R1 and R2/R2 have greater preference and selectivity toward an acetyl group than do the other PAF-AHs.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Activating Factor Acetylhydrolases: Broad Substrate Specificity and Lipoprotein Binding Does Not Modulate the Catalytic Properties of the Plasma Enzyme

et al. 2001

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Platelet-activating factor acetylhydrolases (PAF-AHs) are a group of enzymes that hydrolyze the sn-2 acetyl ester of PAF (phospholipase A 2 activity) but not phospholipids with two long fatty acyl groups. Our previous studies showed that membrane-bound human plasma PAF-AH (pPAF-AH) accesses its substrate only from the aqueous phase, which raises the possibility that this enzyme can hydrolyze a variety of lipid esters that are partially soluble in the aqueous phase. Here we show that pPAF-AH has broad substrate specificity in that it hydrolyzes short-chain diacylglycerols, triacylglycerols, and acetylated alkanols, and displays phospholipase A 1 activity. On the basis of all of the substrate specificity results, it appears that the minimal structural requirement for a good pPAF-AH substrate is the portion of a glyceride derivative that includes an sn-2 ester and a reasonably hydrophobic chain in the position occupied by the sn-1 chain. In vivo, pPAF-AH is bound to high and low density lipoproteins, and we show that the apparent maximal velocity for this enzyme is not influenced by lipoprotein binding and that the enzyme hydrolyzes tributyroylglycerol as well as the recombinant pPAF-AH does. Broad substrate specificity is also observed for the structurally homologous PAF-AH which occurs intracellularly [PAF-AH(II)] as well as for the PAF-AH from the lower eukaryote Physarum polycephalum although pPAF-AH and PAF-AH(II) tolerate the removal of the sn-3 headgroup better than the PAF-AH from P. polycephalum does. In contrast, the intracellular PAF-AH found in mammalian brain [PAF-AH(Ib) R1/R1 and R2/R2 homodimers] is more selectively operative on compounds with a short acetyl chain although this enzyme also displays significant phospholipase A 1 activity.

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The role of lipid peroxidation and antioxidants in oxidative modification of LDL

Cited by 2,146 publications

References 246 publications

Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

Oxidative stress in metabolic syndrome

Platelet-Activating Factor Acetylhydrolases: Broad Substrate Specificity and Lipoprotein Binding Does Not Modulate the Catalytic Properties of the Plasma Enzyme

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