Predisposition to LDL oxidation during copper-catalyzed oxidative modification and its relation to α-tocopherol content in humans

Cominacini, Luciano; Garbin, Ulisse; Cenci, B.; Davoli, A.; Pasini, C.; Ratti, Emiliangelo; Gaviraghi, G.; Cascio, Vincenzo Lo; Pastorino, Antonio M.

doi:10.1016/0009-8981(91)90217-z

Cited by 43 publications

(17 citation statements)

References 20 publications

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“…The amount of LDL antioxidant, under circumstances in which other variables were probably largely unaffected, is therefore critical in increasing the potential of scavenging radicals and thus delaying the initiation of the lipid peroxidation chain. Our data are also consistent with studies in which an increase of LDL antioxidants, by incubation or oral supplementation, always resulted in a strict proportional increase in the length of the lag phase [42][43][44].…”

Section: Discussionsupporting

confidence: 92%

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Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Cominacini

Garbin

Pastorino³

et al. 1997

Diabetologia

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Low density lipoprotein (LDL) oxidation is believed to play an important role in the development of atherosclerotic plaques [1][2][3][4][5]. This view is supported by LDL with characteristics similar to those of oxidatively modified LDL being present in atheromatous lesions [6]. Studies in cultured cells have demonstrated that oxidized LDL is chemotactic for monocytes and stimulates monocyte endothelial cell interaction [7,8]. It can also cause initial endothelial cell damage and increase uptake by scavenger receptors on macrophages, leading to cholesterol accumulation and foam cell formation [7,9].Oxidative modification of LDL is not likely to occur in circulation [3]. In view of the difficulties in identifying oxidized lipoprotein in plasma, many workers have attempted to analyse the oxidation susceptibility of isolated LDL particles in vitro [10,11]. If LDL can penetrate macrophages only after its modification [3], the ability of LDL to resist oxidation could be an Diabetologia (1997) Summary Troglitazone is a new oral antidiabetic agent able to reduce lipid peroxidation. In this study we evaluated its effect on the susceptibility of LDL and HDL to in vitro oxidation induced by copper ions and endothelial cells. In Cu ++ -induced LDL modification, different amounts of troglitazone were added to aliquots of the same pool of plasma with subsequent ultracentrifuge separation of LDL and HDL. Differences in LDL and HDL susceptibility to in vitro oxidation with Cu ++ were studied by measuring the changes in fluorescence intensity (expressed as lag phase). LDL derived from plasma incubated with different amounts of troglitazone were also incubated with umbilical vein endothelial cells (HU-VEC), the modification being monitored by LDL relative electrophoretic mobility and fluorescence. During Cu ++ -and HUVEC-induced LDL oxidation, the decay rate of vitamin E, and the potency of troglitazone as a radical scavenger in comparison with vitamin E were also studied. Troglitazone determined a significant, dose-dependent decrease in Cu ++ -induced LDL and HDL oxidation. Incubation with HUVEC was also followed by a progressive, significant decrease of LDL relative electrophoretic mobility and fluorescence intensity. During Cu ++ -and HU-VEC-induced-LDL modification, troglitazone significantly reduced the rate of vitamin E decay. In this study we also demonstrated that under the same oxidative stress, troglitazone was much more potent as a radical scavenger than vitamin E. In conclusion, the results demonstrate that troglitazone can reduce LDL and HDL in vitro oxidation and that, during this process, it can protect vitamin E. In addition to ensuring blood glucose control, the drug may therefore be useful in inhibiting lipoprotein peroxidation. [Diabetologia (1997)

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Section: Discussionsupporting

confidence: 92%

“…At least for Cu ++ -induced LDL oxidation, this is in agreement with previously reported data [42]. Troglitazone added exogenously to LDL determined dose-dependent reduction of the vitamin E initial decay rate, and thus of LDL vitamin E consumption.…”

Section: Cusupporting

confidence: 93%

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Cominacini

Garbin

Pastorino³

et al. 1997

Diabetologia

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“…This effect was evident at both 1 and 2 weeks of treatment. Our data are consistent with other studies in which an increase of LDL antioxidants, by incubation or oral supplementation, always resulted in a strict proportional increase in the length of the lag phase [14,20,15,30]. Oxidative modification begins only when LDL has been largely depleted of its antioxidants [31], which suggests that the lag phase is mainly determined by the antioxidant content.…”

Section: Discussionsupporting

confidence: 82%

supporting

confidence: 82%

“…This is increased in patient groups with CAD [9,10] and at risk of developing CAD [11,12]. Antioxidant supplementation has been shown to reduce the progression of atherosclerotic lesions in Watanabe hyperlipidaemic rabbits [13] and to increase the resistance of LDL to oxidation in both healthy subjects [14,15] and diabetic subjects [16]. Two large-scale studies have shown that supplementation with high doses of vitamin E was associated with significantly decreased risk of CAD [17,18].…”

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confidence: 99%

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Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers

Cominacini

Young²,

Capriati³

et al. 1997

Diabetologia

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Troglitazone, a thiazolidine-2-dione derivative, is a novel oral anti-diabetic drug under development for the treatment of non-insulin-dependent diabetes (NIDDM). It has been reported to enhance insulin sensitivity [1], increase the conversion of glucose to glycogen in rat HepG2 cells [1], reduce hepatic gluconeogenic enzyme activity in rats and mice [2] and to improve metabolic control in NIDDM patients [3,4].There is a much increased risk of coronary artery disease (CAD) in diabetes and around 60 % of the Diabetologia (1997Diabetologia ( ) 40: 1211Diabetologia ( -1218 Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers Summary The oxidative modification of low density lipoprotein is of importance in atherogenesis. Antioxidant supplementation has been shown, in published work, to increase low density lipoprotein resistance to oxidation in both healthy subjects and diabetic subjects; in animal studies a contemporary reduction in atherogenesis has been demonstrated. Troglitazone is a novel oral antidiabetic drug which has similarities in structure with vitamin E. The present study assessed the effect of troglitazone 400 mg twice daily for 2 weeks on the resistance of low density lipoprotein to oxidation in healthy male subjects. Ten subjects received troglitazone and ten received placebo in a randomised, placebo-controlled, parallel-group design. The lag phase (a measure of the resistance of low density lipoprotein to oxidation) was determined by measurement of fluorescence development during copper-catalysed oxidative modification of low density lipoprotein. The lag phase was increased by 27 % (p < 0.001) at week 1 and by 24 % (p < 0.001) at week 2 in the troglitazone treated group compared with the placebo group. A number of variables known to influence the resistance of low density lipoprotein to oxidation were measured. They included macronutrient consumption, plasma and lipoprotein lipid profile, alpha-tocopherol, beta-carotene levels in low density lipoprotein, low density lipoprotein particle size, mono and polyunsaturated fatty acid content of low density lipoprotein and pre-formed low density lipoprotein hydroperoxide levels in low density lipoprotein. Troglitazone was associated with a significant reduction in the amount of pre-formed low density lipoprotein lipid hydroperoxides. At weeks 1 and 2, the low density lipoprotein hydroperoxide content was 17 % (p < 0.05) and 18 % (p < 0.05) lower in the troglitazone group compared to placebo, respectively. In summary the increase in lag phase duration in the troglitazone group appeared to be due to the compound's activity as an antioxidant and to its ability to reduce the amount of preformed low density lipoprotein lipid hydroperoxides. This antioxidant activity could provide considerable benefit to diabetic patients where atherosclerosis accounts for the majority of total mortality. [Diabetologia (1997) total mortality in diabetes is due to atherosclerosis and subsequent complications [5]. The reasons for th...

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Determination of lipid hydroperoxides in native low-density lipoprotein by a chemiluminescent flow-injection assay

Cominacini

Pastorino²,

McCarthy³

et al. 1993

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

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Predisposition to LDL oxidation during copper-catalyzed oxidative modification and its relation to α-tocopherol content in humans

Cited by 43 publications

References 20 publications

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers

Determination of lipid hydroperoxides in native low-density lipoprotein by a chemiluminescent flow-injection assay

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