Toxicity of oxysterols to human monocyte-macrophages

Clare, K.; Hardwick, Simon J.; Carpenter, Keri L. H.; Weeratunge, Nishanthi; Mitchinson, M. J.

doi:10.1016/0021-9150(95)05594-m

Cited by 126 publications

(66 citation statements)

References 40 publications

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“…[23][24][25][26][27][28][29] Moreover, the major products of cholesterol autoxidation are the most commonly detected oxysterols in foods (7K, 7␣OH, 7␤OH, ␣-EPOX, and ␤-EPOX). 29 Various oxysterols have been detected in extensive amounts in human tissues and fluids, including human plasma, atherogenic lipoproteins, and atherosclerotic plaque.…”

Section: Discussionmentioning

confidence: 99%

“…21,22 Some of the preferred measures of lipid peroxidation in vivo are the cholesterol oxidation products. [23][24][25][26][27][28][29] In 1994, we started a randomized-factorial, doublemasked, placebo-controlled, long-term trial to study the effect of supplementation with vitamins E and C on atherosclerotic progression and the hypothesized pathways of the expected preventive effects. Measurements of in vitro and in vivo lipid peroxidation were carried out at entry and at 12 and 36 months in a subset of 48 male participants.…”

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confidence: 99%

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Long-Term Effects of Vitamin E, Vitamin C, and Combined Supplementation on Urinary 7-Hydro-8-Oxo-2′-Deoxyguanosine, Serum Cholesterol Oxidation Products, and Oxidation Resistance of Lipids in Nondepleted Men

Porkkala-Sarataho

Salonen

Nyyssönen

et al. 2000

ATVB

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Abstract-We studied the long-term effects of vitamins E and C and their combination on lipid peroxidation in vivo and in vitro. The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) trial is a double-masked placebo-controlled randomized clinical trial to study the effects of vitamin C (500 mg of slow release ascorbate per day), vitamin E (182 mg of RRR-␣-tocopherol acetate per day), and the combination of both antioxidants. Lipid peroxidation measurements were carried out for 48 male participants at entry and at 12 and 36 months. Compared with placebo, vitamin E and the vitamin combination increased plasma lipid-standardized ␣-tocopherol during the first 12 months by 68.2% and 65.2% (PϽ0.001 for both), respectively, and reduced serum 7␤-hydroxycholesterol by 50.4% (Pϭ0.013) and 44.0% (Pϭ0.041), respectively. The net change of lipid standardized ␣-tocopherol was 63.8% after 36 months of vitamin E supplementation and 43.3% for the combination. Vitamin C supplementation elevated plasma total ascorbate level by 30.1% (Pϭ0.043) in 12 months and by 91.1% (Pϭ0.001) in 36 months.Neither vitamin E, vitamin C, nor the combination influenced the urinary excretion rate of 7-hydro-8-oxo-2Ј-deoxyguanosine or the antioxidative capacity of plasma. Vitamin E and the combination of vitamins E and C enhanced the oxidation resistance of isolated lipoproteins and total serum lipids. Our data indicate that long-term supplementation of nondepleted men with a reasonable dose of vitamin E alone or in combination with slow release vitamin C reduces lipid peroxidation in vitro and in vivo, whereas a relatively high dose of vitamin C alone does not. Key Words: antioxidants Ⅲ lipid peroxidation Ⅲ oxidation resistance Ⅲ 7-hydro-8-oxo-2Ј-deoxyguanosine Ⅲ oxysterols V itamins E 1-4 and C 5,6 are widely regarded as important dietary antioxidants. However, this concept is based on in vitro studies and on supplementation trials in which only measurements of lipid peroxidation ex vivo have been performed. 3 The evidence of the lipid peroxidation-inhibiting effects of vitamins E and C in vitro is plentiful. [1][2][3][4][5][6][7] In addition, oral vitamin E supplementation has consistently increased the oxidation resistance of isolated lipoproteins in vitro. 8 -13 Vitamin C has had been shown to have a similar effect in a few 14 -16 but not in all 17 studies. Vitamin C can also act as a pro-oxidant in certain conditions. 17,18 In theory, vitamin E could function as a mediator of lipid peroxidation if sufficient coantioxidants are not present. 19,20 However, this theory has not been tested in oral supplementation studies with in vivo measurements. There are no previous long-term placebocontrolled oral supplementation trials concerning the effects of these vitamins on lipid peroxidation in nonsmoking clinically healthy subjects.The assessment of oxidative stress and lipid peroxidation in vivo in humans is problematic. 7-Hydro-8-oxo-2Ј-deoxyguanosine (8-oxodG), a repair product of oxidative damage to DNA, has been used as an indicator...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Long-Term Effects of Vitamin E, Vitamin C, and Combined Supplementation on Urinary 7-Hydro-8-Oxo-2′-Deoxyguanosine, Serum Cholesterol Oxidation Products, and Oxidation Resistance of Lipids in Nondepleted Men

Porkkala-Sarataho

Salonen

Nyyssönen

et al. 2000

ATVB

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“…In addition to aldehydes, oxidised LDL contains other cytotoxic components, e.g. lipid hydroperoxides and oxysterols [23,24]. Thus toxicity of oxidised LDL could arise from the combined effect of these and other as yet unidentified cytotoxins.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and chemotactic potencies of several aldehydic components of oxidised low density lipoprotein for human monocyte‐macrophages

et al. 1996

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“…Such discrepancies may have arisen from addition of fetal calf serum to the incubation medium by the aforementioned authors 45 ; the underlying mechanism remains indeterminate, however. The cytotoxicity of oxysterols to various cell types has been documented and evaluated in human monocyte-derived macrophages, 56 in which oxysterols may activate apoptosis. At the low dose of oxysterols (5 g/mL) that we used, toxicity was not detectable; however, they became toxic at the higher concentrations that we tested (Ͼ7.5 g/mL).…”

Section: Time Course Of Evolution Of Oxidation Parameters and Phosphomentioning

confidence: 99%

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

Stengel

Antonucci

Gaoua

et al. 1998

ATVB

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Abstract-The regulation of macrophage lipoprotein lipase (LPL) secretion and mRNA expression by atherogenic lipoproteins is of critical relevance to foam cell formation. LPL is present in arterial lesions and constitutes a bridging ligand between lipoproteins, proteoglycans, and cell receptors, thus favoring macrophage lipoprotein uptake and lipid accumulation. We investigated the effects of native and of oxidized lipoproteins on the expression of LPL in an in vitro human monocyte-macrophage system. Exposure of mature macrophages (day 12) to highly copper-oxidized human low density lipoprotein (LDL) (100 g protein per milliliter) led to marked reduction in the expression of LPL activity (Ϫ62%, PϽ0.01) and mRNA level (Ϫ47%, PϽ0.05); native LDL, acetylated LDL, and LDL oxidized for Ͻ6 hours were without effect. The reduction in LPL activity became significant at a threshold of 6 hours of LDL oxidation (Ϫ31%, PϽ0.05). Among the biologically active sterols formed during LDL oxidation, only 7␤-hydroxycholesterol (5 g/mL) induced a minor reduction in macrophage LPL activity, whereas 25-hydroxycholesterol was without effect. By contrast, lysophosphatidylcholine, whose LDL content increased in parallel with the degree of oxidation, induced significant reductions in LPL activity and mRNA levels at concentrations of 2 to 20 mol/L (Ϫ34% to Ϫ53%, PϽ0.01).Our results demonstrate that highly oxidized LDL (Ͼ6-hour oxidation) exerts negative feedback on LPL secretion in human monocytes-macrophages via a reduction in mRNA levels. By contrast, native LDL and mildly oxidized LDL (Ͻ6-hour oxidation) did not exert a feedback effect on LPL expression. We speculate that the content of lysophosphatidylcholine and, to a lesser degree, of 7␤-hydroxycholesterol in oxidized LDLs is responsible for the downregulation of LPL activity and mRNA abundance in human monocyte-derived macrophages and may therefore modulate LPL-mediated pathways of lipoprotein uptake during conversion of macrophages to foam cells. 2-5The mechanism of the conversion of macrophages to foam cells containing large amounts of cholesterol, cholesteryl esters, and TGs is presently the subject of extensive investigation. 6 The uptake of lipoproteins by such cells involves several receptors of distinct specificity, including scavenger receptors, 7 CD36, 8 and Fc receptors 9 for oxLDL; the LDL receptor; the LDL receptor-related protein receptor 10,11 ; the VLDL receptor for TG-rich lipoproteins 12 ; and last, membrane-binding proteins for uptake of certain TG-rich lipoproteins. 13 These cellular uptake mechanisms are rendered complex by the contribution of additional factors such as heparan sulfate proteoglycans of the matrix and cell plasma membranes and equally by LPL, 14 which may serve to "anchor" lipoproteins to the cell surface.LPL is a key enzyme of lipoprotein metabolism that hydrolyzes the TG component of chylomicrons and VLDL. 15 Moreover, LPL can act as a ligand to create a "bridge" between TG-rich lipoproteins and several receptors of the LDL family.16 LPL may al...

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Toxicity of oxysterols to human monocyte-macrophages

Cited by 126 publications

References 40 publications

Long-Term Effects of Vitamin E, Vitamin C, and Combined Supplementation on Urinary 7-Hydro-8-Oxo-2′-Deoxyguanosine, Serum Cholesterol Oxidation Products, and Oxidation Resistance of Lipids in Nondepleted Men

Long-Term Effects of Vitamin E, Vitamin C, and Combined Supplementation on Urinary 7-Hydro-8-Oxo-2′-Deoxyguanosine, Serum Cholesterol Oxidation Products, and Oxidation Resistance of Lipids in Nondepleted Men

Cytotoxic and chemotactic potencies of several aldehydic components of oxidised low density lipoprotein for human monocyte‐macrophages

Inhibition of LPL Expression in Human Monocyte–Derived Macrophages Is Dependent on LDL Oxidation State

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