The oxidative modification hypothesis of atherogenesis: an overview

Chisolm, Guy M.; Steinberg, Daniel

doi:10.1016/s0891-5849(00)00344-0

Cited by 688 publications

(428 citation statements)

References 128 publications

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“…Oxidative stress and lipid peroxidation are widely believed to play a significant role in the atherosclerotic process [2,9,19,20] And yet, prospective randomized intervention studies utilizing anti-oxidant supplementation such as α-tocopherol have, on the whole, failed to demonstrate clinical benefit [8,10]. Importantly, in human studies where large doses of α-tocopherol have been used and oxidative products monitored, no reduction in systemic markers of oxidant stress have been noted [21].…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative modification of low-density lipoprotein and subsequent formation of foam cells are thought to be an initial step in atherogenesis. Multiple animal and in vitro studies have further supported the role of oxidative processes in virtually all phases of coronary artery disease (CAD), from foam cell formation to plaque rupture and thrombosis [1][2][3][4][5][6][7][8][9]. However, recent clinical data from large randomized studies have on the whole failed to demonstrate a significant reduction in clinical events after treatment with "antioxidant" interventions, such as supplementation with α-tocopherol [10].…”

Section: Introductionmentioning

confidence: 99%

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Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease

Shishehbor

Zhang

Medina

et al. 2006

Free Radical Biology and Medicine

113

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Oxidant stress is widely believed to participate in cardiovascular disease pathogenesis. However, progress in defining appropriate systemic anti-oxidant targetted therapies has been hindered by uncertainty in defining clinically relevant systemic oxidant stress measures. In a case control study, 50 subjects with CAD (> 50% stenosis in one or more major coronary vessels) and 54 without CAD (< 30% stenosis in all major coronary vessels) were tested. Plasma was isolated and stored under conditions designed to prevent artificial lipid peroxidation. Systemic levels of multiple (n=9) specific fatty acid oxidation products including individual hydroxy-octadecadienoic acids (HODEs), hydroxy-eicosatetraenoic acids (HETEs), and F 2 -Isoprostanes, were simultaneously measured by high performance liquid chromatography (HPLC) with on-line tandem mass spectrometry, along with traditional risk factors and C-reactive protein (CRP) levels. Of the markers monitored, only 9-HETE and F 2 -Isoprostanes, both products of free radical-mediated arachidonic acid oxidation, were significantly elevated in patients with angiographically defined CAD (9-HETE, 8.7 ± 4 vs. 6.8 ± 4 umol/mol arachidonate, p = 0.011; and F 2 -Isoprostanes, 9.4 ± 5 vs. 6.2 ± 3umol/mol arachidonate, p < 0.001). In multivariable analyses with simultaneous adjustment for Framingham Risk Score and C-reactive protein, 9-HETE (4 th quartile OR=4.8, 95% CI=1.3 to 17.1; P = 0.016) and F 2 -Isoprostanes (4 th quartile OR=9.7, 95% CI=2.56 to 36.9; P < 0.001) remained strong and independent predictors of CAD risk. Systemic levels of 9-HETE and F 2 -Isoprostanes are independently associated with angiographic evidence of CAD and appear superior to other specific oxidation products of arachidonic and linoleic acids as predictors of the presence of angiographically evident coronary artery disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease

Shishehbor

Zhang

Medina

et al. 2006

Free Radical Biology and Medicine

113

View full text Add to dashboard Cite

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“…The oxidative modification of low density lipoprotein (LDL) is believed widely to be involved in the pathogenesis of human atherosclerosis [1], the underlying cause of coronary heart disease and most strokes. A number of large clinical trials have shown no decrease in cardiovascular disease after antioxidant supplementation, however, and the importance of oxidised LDL in atherosclerosis is therefore an unresolved issue [2].…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have demonstrated that LDL can be oxidised in vitro by cells associated with atherosclerotic lesions [3][4][5][6][7]. The mechanisms of LDL oxidation in vivo are controversial [1]. Possibilities to explain how LDL is oxidised in atherosclerotic lesions include lipoxygenase, myeloperoxidase/nitrite, peroxynitrite, NADPH oxidase, xanthine oxidase, mitochondrial respiration, iron or copper [8].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the antioxidant to pro-oxidant switch in the behavior of dehydroascorbate during LDL oxidation by copper(II) ions

Horsley

Burkitt

Jones

et al. 2007

Archives of Biochemistry and Biophysics

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Subject area: Systems biochemistryAbbreviations: BCDS, bathocuproine disulphonic acid; DMPO,5, EPR, electron paramagnetic resonance; 13-HPODE, 13(S)-hydroperoxyoctadeca-9Z,11E-dienoic acid 2 ABSTRACTOxidised low density lipoprotein (LDL) may be involved in the pathogenesis of atherosclerosis.We have therefore investigated the mechanisms underlying the antioxidant/pro-oxidant behavior of dehydroascorbate, the oxidation product of ascorbic acid, toward LDL incubated with Cu 2+ ions. By monitoring lipid peroxidation through the formation of conjugated dienes and lipid hydroperoxides, we show that the pro-oxidant activity of dehydroascorbate is critically dependent on the presence of lipid hydroperoxides, which accumulate during the early stages of oxidation.Using electron paramagnetic resonance spectroscopy, we show that dehydroascorbate amplifies the generation of alkoxyl radicals during the interaction of copper ions with the model alkyl hydroperoxide, tert-butylhydroperoxide. Under continuous-flow conditions, a prominent doublet signal was detected, which we attribute to both the erythroascorbate and ascorbate free radicals.On this basis, we propose that the pro-oxidant activity of dehydroascorbate toward LDL is due to its known spontaneous interconversion to erythroascorbate and ascorbate, which reduce Cu 2+ to Cu + and thereby promote the decomposition of lipid hydroperoxides. Various mechanisms, including copper chelation and Cu + oxidation, are suggested to underlie the antioxidant behavior of dehydroascorbate in LDL that is essentially free of lipid hydroperoxides.

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“…those from glycation) and oxidation of free glucose and its products. Each mechanism can generate free radicals that can modify LDL, and hence potentially play a role in the enhanced cellular uptake of modified LDL [12,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

et al. 2006

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Aims/hypothesis: Previous studies have shown that glycation of LDL by methylglyoxal and glycolaldehyde, in the absence of significant oxidation, results in lipid accumulation in macrophage cells. Such 'foam cells' are a hallmark of atherosclerosis. In this study we examined whether LDL glycation by methylglyoxal or glycolaldehyde, and subsequent lipid loading of cells, can be inhibited by agents that scavenge reactive carbonyls. Such compounds may have therapeutic potential in diabetesassociated atherosclerosis. Materials and methods: LDL was glycated with methylglyoxal or glycolaldehyde in the absence or presence of metformin, aminoguanidine, Girard's reagents P and T, or hydralazine. LDL modification was characterised by changes in mobility (agarose gel electrophoresis), cross-linking (SDS-PAGE) and loss of amino acid residues (HPLC). Accumulation of cholesterol and cholesteryl esters in murine macrophages was assessed by HPLC. Results: Inhibition of LDL glycation was detected with equimolar or greater concentrations of the scavengers over the reactive carbonyl. This inhibition was structure-dependent and accompanied by a modulation of cholesterol and cholesteryl ester accumulation. With aminoguanidine, Girard's reagent P and hydralazine, cellular sterol levels returned to control levels despite incomplete inhibition of LDL modification. Conclusions/ interpretation: Inhibition of LDL glycation by interception of the reactive aldehydes that induce LDL modification prevents lipid loading and model foam cell formation in murine macrophage cells. Carbonyl-scavenging reagents, such as hydrazines, may therefore help inhibit LDL glycation in vivo and prevent diabetes-induced atherosclerosis.

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The oxidative modification hypothesis of atherogenesis: an overview

Cited by 688 publications

References 128 publications

Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease

Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease

Mechanism of the antioxidant to pro-oxidant switch in the behavior of dehydroascorbate during LDL oxidation by copper(II) ions

Hydrazine compounds inhibit glycation of low-density lipoproteins and prevent the in vitro formation of model foam cells from glycolaldehyde-modified low-density lipoproteins

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