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Red Wine Inhibits the Cell-Mediated Oxidation of LDL and HDL

Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey

Address reprint requests to: Vincent A. Rifici, PhD, Department of Medicine, Medical Education Building, Robert Wood Johnson Medical School, New Brunswick, NJ 08903-0019

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
Objective: We compared the in vitro effects of red wine, white wine and ethanol on the cell mediated oxidation of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) by three frequently-used assays.

Methods: LDL and HDL isolated from normolipidemic human serum were incubated with J774.A1 macrophages in DMEM with copper, with or without red wine, white wine or ethanol (equivalent to 0.2 mg ethanol/ml). Lipoprotein oxidation was assessed by conjugated diene formation as measured by changes in absorbance at 234 nm (A234), thiobarbituric-acid-reactive-substance (TBARS) production and trinitrobenzene-sulfonic-acid (TNBS) reactivity.

Results: Red wine (0.2 mg ethanol/mL) inhibited LDL oxidation as indicated by an 85.7% decrease in absorbance at 234 nm, a 96.5% decrease in TBARS production and complete prevention of the decrease in TNBS reactivity. White wine and ethanol did not have any significant effect at 0.2 mg/mL. White wine at 1.0 mg ethanol/mL inhibited TBARS production from LDL by 84.1%. Red wine (0.2 mg ethanol/mL) inhibited HDL oxidation as indicated by a 78.9% decrease in A234, an 81.7% decrease in TBARS production and by no change in TNBS reactivity. White wine and ethanol had no effect at 0.2 mg/mL. White wine at 1.0 mg ethanol/mL inhibited TBARS production from HDL by 66.4%.

Conclusions: These results indicate that red wine inhibits the cell mediated oxidation of lipoproteins, that white wine is not as effective as red wine and that the effect of the red wine is not due to its ethanol content.

Key words: low density lipoprotein, high density lipoprotein, wine, macrophage, oxidation

	INTRODUCTION

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The oxidative modification of low density lipoprotein (LDL) and its unregulated and accelerated uptake by artery wall macrophages have been implicated in the development of atherosclerosis [1]. LDL oxidation has been demonstrated in vitro [2–4], and there is evidence that LDL oxidation occurs in vivo [5–7]. While the oxidation of high density lipoprotein (HDL) has been the subject of relatively few experiments, the results of in vitro studies suggest that HDL oxidation also occurs in vivo [8,9]. Oxidation of HDL diminishes its capacity to mediate cholesterol efflux from various cell types [10–12] and we have previously demonstrated a significant negative correlation between the extent of HDL oxidation and cholesterol efflux [13]. The results of epidemiological studies indicate an inverse relationship between plasma concentrations of the antioxidant vitamins and mortality from coronary artery disease, suggesting that dietary antioxidants are anti-atherosclerotic agents [14]. Dietary supplementation with antioxidant vitamins decreases the ex vivo susceptibility of LDL to oxidation [15–17]. We have reported previously that dietary administration of antioxidant vitamins decreases the susceptibility of HDL to oxidation ex vivo and decreases the loss of its cholesterol efflux capacity which results from oxidation [18].

Epidemiologic studies have indicated that moderate alcohol consumption results in diminished risk of coronary artery disease [19]. The interest in red wine as an anti-atherosclerotic agent stems from epidemiological evidence that the occurrence of coronary artery disease in France, where consumption of red wine is high, is lower than in other countries where serum lipoprotein concentrations, dietary saturated fat and alcohol consumption are comparable. This observation is referred to as the "French paradox" [20,21]. These reports suggest that wine has a greater protective effect against coronary artery disease than can be attributed to its alcohol content. However, consumption of alcohol in any form may be beneficial, and there may be several mechanisms mediating the beneficial effects [22]. Red wine contains several flavonoids, which are polyphenols that exert chain-breaking anti-oxidant activity by donating a hydrogen to react with hydroxyl, superoxide and lipid peroxyl radicals [23,24], suggesting that one beneficial effect of red wine is to inhibit the in vivo oxidation of lipoproteins. Fuhrman et al. [25] reported that red wine, but not white wine, inhibited the formation of thiobarbituric acid reactive substances in vitro during the copper mediated oxidation of LDL. Frankel et al. [26] measured the formation of conjugated dienes and hexanal from the copper catalyzed oxidation of LDL and demonstrated that polyphenols extracted from red wine inhibit oxidation more effectively than -tocopherol. The phenolic compounds inhibited oxidation by scavenging lipid peroxyl radicals and not by chelating copper [26].

In the present study, we demonstrate that the J774.A1 macrophage cell line stimulates lipoprotein oxidation in the presence of copper and use these cells to study the effects of red wine, white wine and ethanol on the oxidation of LDL and HDL.

	MATERIALS AND METHODS

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Chemicals
Phosphate buffered saline (PBS), Dulbecco’s minimum essential medium (DMEM), bovine calf serum, tetramethoxypropane, thiobarbituric acid, trinitrobenzene sulfonic acid, butylated hydroxytoluene (BHT), lipid determination kits and Hank’s balanced salt solution were obtained from Sigma Chemical (St. Louis, MO). Trichloroacetic acid and copper nitrate solution (1 mg/mL) were from Fisher Scientific (Springfield, NJ). Bicinchoninic acid (BCA) protein assay reagents were from Pierce (Rockford, IL). Total antioxidant status assay kit was from Wak-Chemie Medical GMBH (Bad Soden, Germany). Cabernet Sauvignon (12.5% alcohol by volume or 99 mg ethanol/mL) and Chardonnay (13.0% alcohol by volume or 103 mg ethanol/mL) were from Robert Mondavi (Woodbridge, CA). The sulfite contents of these wines were equal. Additional wines are mentioned below when used.

Cell Culture
Murine monocyte-derived J774.AI macrophages were maintained in culture in DMEM with phenol red and 10% bovine calf serum, 100 U/mL penicillin and 100 µg/mL streptomycin at 37°C under 5% CO₂ in air. Cells (2 x 10⁵/mL) were plated in DMEM with 10% bovine calf serum with antibiotics. Medium was also added to wells without cells. After eight hours, the wells were washed with serum-free Hank’s balanced salt solution without phenol red before incubation with LDL and HDL.

Lipoprotein Preparation
Serum was obtained from a fasting male volunteer whose serum lipid concentrations were triacylglycerol, 63 mg/dL; total cholesterol, 204 mg/dL; HDL cholesterol, 61 mg/dL. The subject maintained a constant diet and level of physical activity and did not consume any antioxidant vitamin supplements, wine or other alcoholic beverages. Serum concentrations of vitamins C and E in this subject were determined previously [described in ref. 18] and were 10.0 µg/mL and 10.8 µg/mL respectively. Total antioxidant status of the serum of this individual was 1.60 mM. The reported total antioxidant status of a normal adult reference population was 1.46 ± 0.14 mM [27]. LDL (1.019 g/mL < d < 1.063 g/mL) and HDL (1.063 g/mL < d < 1.21 g/mL) were isolated by sequential ultracentrifugation from serum [28] as previously described [29]. After isolation, the lipoproteins were dialyzed and filtered. Protein content of the fractions were estimated by the bicinchoninic acid method. Phospholipid, cholesterol and triacylglycerol content were determined by enzymatic methods. The chemical composition (weight %) of LDL was 27% protein, 35% cholesterol, 23% phospholipid and 15% triacylglycerol and of HDL was 52% protein, 23% cholesterol, 23% phospholipid and 2% triacylglycerol. Vitamin E concentrations in lipoprotein fractions isolated from this subject were determined previously [17,18]. The value for LDL was 5.7 µg/mg and for HDL was 2.7 µg/mg protein.

Lipoprotein Oxidation
LDL and HDL were dialyzed at 4°C against PBS with calcium, magnesium and 10 mM sodium bicarbonate, pH 7.4. Incubations were done at 37°C in serum-free DMEM without phenol red. Our preliminary experiments (data not shown) and results reported by others [30] demonstrate that copper is required to catalyze lipoprotein oxidation in this medium. LDL (0.2 mg protein/ml) was incubated without and with macrophages (500,000 cells/well) in 6-well plates or in 24-well plates (200,000 cells/well) for 16 hours in serum-free DMEM containing 2 µM copper. HDL (0.5 mg protein/mL) was incubated without and with macrophages as above for 24 hours in serum-free DMEM containing 5 µM copper. Wine or ethanol were added in amounts equivalent to 0.2 mg ethanol/mL or as indicated for concentration dependency studies. Samples of media were taken for assays of LDL and HDL oxidation. Incubation with wines or ethanol had no effect on the appearance of cells or their adherence to the incubation wells as determined by light microscopy.

Assays of LDL and HDL Oxidation
Lipoprotein oxidation in samples of media was quantified by conjugated diene formation measured by change in absorbance at 234 nm (A234), thiobarbituric acid reactive substance (TBARS) production and loss of trinitrobenzene sulfonic acid (TNBS) reactivity as previously described [29]. Change in absorbance at 234 nm was determined after a 1/10 dilution [31]. TBARS are expressed as nanomoles malondialdehyde (MDA) equivalents per milligram protein compared with tetramethoxypropane standards [32]. TNBS reactive lysine amino groups is expressed as a percent of that in unincubated, unmodified lipoprotein [33]. Samples of incubation media were dialyzed against 0.01% EDTA, 150 mM sodium chloride and 10 mM sodium bicarbonate, pH 7.6 before being assayed for A234 and TNBS reactivity.

Statistics
Analyses of data were performed using the SAS system. Comparisons were done by an analysis of variance. Where significant effects were found, a Duncan’s analysis was done for individual comparisons. Results are expressed as mean ± standard error of the mean, or as noted.

	RESULTS

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The oxidation of LDL in the absence and presence of J774 macrophages for 16 hours was determined. In the presence of cells, LDL oxidation measured by A234, TBARS production and loss of TNBS reactivity was 2.3, 7.3 and 3.0 fold higher respectively, compared to incubations in the absence of cells (Fig. 1). The results of the incubation of LDL in the presence and absence of red wine, white wine and ethanol at 0.2 mg ethanol/ml are also shown in Fig. 1. Addition of red wine inhibited conjugated diene formation by 85.7% as indicated by a decrease in A234 (p < 0.0001). White wine and ethanol had no effect (Fig. 1A). There was a 96.5% reduction in cell mediated TBARS production with the addition of red wine (p < 0.0001). White wine produced a 20.1% reduction, while the addition of ethanol resulted in a 7.4% increase in TBARS production, neither significantly different compared to control cells incubated in the absence of wine and ethanol (Fig. 1B). Red wine completely prevented the decrease in TNBS reactivity, whereas 36.0%, 27.4% and 32.9% reductions (p < 0.006 compared to red wine) were measured in the media from control incubations and incubations in the presence of white wine and ethanol, respectively (Fig. 1C).

View larger version (19K): [in this window] [in a new window]   Fig. 1. Effects of red wine, white wine and ethanol (equivalent to 0.2 mg/mL ethanol) on LDL oxidation. LDL (0.2 mg protein/mL) was incubated with and without cells in 6 well plates (500,000 cells/well) for 16 h at 37°C in serum-free DMEM containing 2 µM copper. (A) Change in absorbance at 234 nm (A234) is expressed relative to unmodified LDL. (B) TBARS are expressed as nmoles malondialdehyde (MDA) equivalents/mg LDL protein. (C) percent decrease in TNBS reactivity relative to the unmodified LDL (0%). The mean absorbance of the unmodified LDL (50 µg) at 340 nm = 0.164 ± 0.005. Results are means ± SEM of four experiments done in triplicate. Red wine vs. control, white wine and ethanol (A), p < 0.0001; (B), p < 0.0001; (C), p < 0.0006. RW = red wine; WW = white wine; EtOH = ethanol.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Concentration-dependent effect of red wine and white wine on cell mediated oxidation of LDL. Incubation conditions were as described in the legend to Fig. 1 except for incubation in 24-well plates (200,000 cells/well). The mean TBARS production by the cell control (represented as 100%) = 15.1 ± 2.4 nmoles MDA/mg LDL protein. The points are the means ± SEM of four determinations done in triplicate. Red wine vs. white wine in the range of 0.05–0.5 mg EtOH/mL, p < 0.001, at 1.0 mg/mL, NS. RW = red wine; WW = white wine.

View larger version (25K): [in this window] [in a new window]   Fig. 3. Time course of LDL oxidation. Incubation conditions were as described in the legend to Fig. 1 except for incubation in 24-well plates (200,000 cells/well). (A) Change in absorbance at 234 nm (A234) is expressed relative to unmodified LDL. (B) TBARS are expressed as nmoles MDA equivalents/mg LDL protein. Results are from one duplicate experiment. RW = red wine; WW = white wine.

View larger version (19K): [in this window] [in a new window]   Fig. 4. Effects of red wine, white wine and ethanol (equivalent to 0.2 mg/mL ethanol) on HDL oxidation. HDL (0.5 mg protein/mL) was incubated with and without cells in 6 well plates (500,000 cells/well) for 24 h at 37°C in serum-free DMEM containing 5 µM copper. (A) Change in absorbance at 234 nm (A234) is expressed relative to unmodified HDL. Results are means ± SEM of four experiments done in triplicate. (B) TBARS are expressed as nmoles malondialdehyde equivalents/mg HDL protein. (C) % decrease in TNBS reactivity relative to the unmodified HDL (0%). The mean absorbance of the unmodified HDL (50 µg) at 340 nm = 0.243 ± 0.040. Red wine media vs. control, white wine and ethanol (A) p < 0.0001; (B), p < 0.0001; (C) p < 0.007. RW = red wine; WW = white wine; EtOH = ethanol.

View larger version (22K): [in this window] [in a new window]   Fig. 5. TBARS production from HDL oxidation at various concentrations of red and white wines. The incubation conditions were as described in the legend for Fig. 4 except for incubation in 24-well plates (200,000 cells/well). The mean TBARS production by the cell control (represented as 100%) = 9.7 ± 0.7 nmoles MDA/mg HDL protein. The results are the means ± SEM of four determinations done in duplicate. Red wine vs. white wine in the range of 0.05–0.5 mg EtOH/mL, p < 0.007, at 1.0 mg EtOH/mL, p = 0.0534 RW = red wine; WW = white wine.

	DISCUSSION

Our results indicate that red wine inhibits the cell mediated oxidation of lipoproteins in vitro, that white wine is not as effective as red wine and that the effect of the red wine is not due to its ethanol content. The antioxidant components of red wine include the polyphenol flavonoids catechin and quercetin and the phytoalexin resveratrol. These components have been shown to inhibit copper-catalyzed or cell-mediated oxidation of LDL in vitro [34–36]. Our experiments do not elucidate the mechanism of this antioxidant activity. Possible mechanisms by which wine could inhibit oxidation include chelation of copper or scavenging of lipid peroxyl radicals. In studies performed in the absence of cells, red wine at a concentration of 0.1% inhibited copper catalyzed oxidation of LDL, while white wine at 1.0% had no inhibitory effect [37]. Red wine added in vitro also decreased the susceptibility of plasma to oxidation initiated by a free radical generator [25,37].

While there is strong evidence that red wine inhibits lipoprotein oxidation in vitro, the data on the effects of consumption of red wine on the ex vivo susceptibility of lipoproteins to oxidation are conflicting [38]. Flavonoids are capable of entering phospholipid bilayers [24] and thus could associate with lipoproteins. Kondo et al. [39] reported that administration of red wine at an amount equivalent to 0.8 g/kg for 14 days resulted in an increased resistance of LDL to oxidation compared to samples obtained before administration of the wine. Similarly Fuhrman et al. [25] showed that plasma and LDL obtained from subjects following the consumption of 400 ml of red wine for 14 days was less susceptible to oxidation. Consumption of white wine, which does not have as high a content of flavonoids [23], did not have similar effects [25]. In contrast, deRijke et al. [37] reported that consumption of red wine with a reduced ethanol content did not result in a decrease in the ex vivo susceptibility of LDL to oxidation. The extent of inhibition of ex vivo lipoprotein oxidation by red wine would depend on whether the wine flavonoids remain associated with lipoprotein particles during their isolation, as has been shown to occur with vitamin E [17,18]. However, it may not be necessary for flavonoids to bind to lipoproteins in vivo because they could inhibit oxidation when present in serum or the arterial wall. Assays based on the susceptibility of whole serum to oxidation may be more appropriate, and it has been reported that consumption of red wine increases the total antioxidant capacity of serum [40]. At present such assays are not as well characterized as those with isolated lipoproteins, and further studies are needed to characterize the antioxidant effects of the consumption of red wine.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 
Our results indicate that red wine, at a concentration attained in serum with moderate consumption, almost completely inhibits LDL and HDL oxidation mediated by J774 macrophages in vitro. While it is established that oxidized LDL exists in vivo and contributes to the formation of the atherosclerotic plaque, the extent of the in vivo oxidation of HDL and its role in atherogenesis are unknown. In vitro oxidation of HDL diminishes its capacity to mediate cholesterol efflux from macrophages and the administration of antioxidant vitamins inhibits the ex vivo oxidation of HDL and the loss of its efflux capacity. If oxidation of HDL diminishes its antiatherogenic properties, our results would suggest that red wine consumption may be beneficial by inhibiting the oxidation of both HDL and LDL.

	ACKNOWLEDGMENTS

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The authors thank Shelley Greenhaus for clinical assistance.

Received July 1, 1998. Accepted September 1, 1998.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

 

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This Article Abstract Figures Only Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rifici, V. A. Articles by Khachadurian, A. K. Search for Related Content PubMed PubMed Citation Articles by Rifici, V. A. Articles by Khachadurian, A. K.