Atherosclerosis and Lipoproteins |
From the Department of Internal Medicine (R.B.W., B.S.V., R.A.A.), Section of Gastroenterology, the General Clinical Research Center (J.E.S.), and the Department of Biochemistry (M.J.T.), Wake Forest University School of Medicine, Winston-Salem, NC.
| Abstract |
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(PGF2
) were determined after 3 weeks on each
diet. The safflower oil diet increased total
F2-isoprostanes from 53.0±7.2 to 116.2±11.2
nmol/L and PGF2
from 3.5±0.2 to 5.5±0.5
nmol/L, without changing LDL oxidation parameters. Addition
of vitamin E prolonged mean LDL oxidation lag time but, paradoxically,
further increased F2-isoprostanes to 188.2±10.9
nmol/L and PGF2
to 7.8±0.4 nmol/L. These
data suggest that vitamin E may function as a pro-oxidant in cigarette
smokers consuming a high polyunsaturated fat
diet.
Key Words: LDL lipid oxidation antioxidants
-tocopherol F2-isoprostanes
| Introduction |
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-tocopherol, confer dose-dependant protection against
ASCVD,3 4 5
yet prospective intervention
trials6 7 8
have failed to observe a protective effect. Tobacco use is one of the most potent risk factors for ASCVD. The high concentration of free radical oxidants in tobacco smoke9 and the fact that the impact of smoking on the incidence ASCVD correlates with plasma LDL levels10 11 are consistent with the concept that LDL peroxidation by cigarette smoke promotes atherogenesis.12 Indeed, measures of lipid oxidation, such as thiobarbituric acidreactive substances (TBARS) in plasma,13 LDL,14 15 16 and red blood cells17 ; breath alkane excretion18 19 20 ; and F2-isoprostanes in urine21 and plasma,22 are increased in cigarette smokers. Conversely, plasma levels of antioxidant vitamins in smokers, which could protect LDL against the damaging effects of free radicals, are depressed.23
Cigarette smokers thus constitute a high-risk population in which intervention could reduce the risk of ASCVD. Diets high in monounsaturated fatty acid (MUFA) or polyunsaturated fatty acid (PUFA) effectively lower plasma LDL,24 but high PUFA diets constitute a theoretical risk, because PUFAs are excellent substrates for lipid peroxidation.25 Indeed, studies in cigarette smokers15 and in nonsmokers26 27 have found that PUFAs increase LDL oxidation rate and also breath pentane excretion.28
The deleterious impact of dietary PUFA on lipid oxidation, in theory, could be mitigated by concomitant supplementation with antioxidant vitamins. However, although antioxidant vitamins are generally considered to be nontoxic,29 vitamin E is a redox reagent that can function as a pro-oxidant under certain conditions.30 31 32 This has led some to voice concerns that antioxidant vitamins could function as pro-oxidants in vivo.33 34 The fact that prospective studies have failed to show a protective effect of vitamin E against ASCVD7 8 35 and have even suggested that it increases the risk of cardiovascular events in smokers6 35 36 lends credence to these concerns and warrants an examination of the interaction of vitamin E and diet in cigarette smokers.
To this end, we have investigated the effects of a high PUFA diet and vitamin E supplementation on oxidation stress in cigarette smokers by using 2 informative measures: the kinetics of in vitro copper-catalyzed LDL peroxidation, the most frequently used method to assess the effects of diet and antioxidants on lipid oxidation,27 37 38 39 40 41 42 and the plasma concentration of F2-isoprostanes, which are biologically active prostanoids formed by free radialinitiated rearrangement of arachidonic acid,43 and which may be a much better indicator of global in vivo oxygen-derived free radical stress.44
| Methods |
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Study Design
The present study was conducted in the General
Clinical Research Center of the Wake Forest University School of
Medicine. During the study, the subjects ate only food prepared by the
metabolic kitchen and used no ad libitum vitamin
supplements. Daily energy requirements were estimated by the
Harris Benedict equation. Subjects were weighed daily, and the
total caloric content of each diet was adjusted, if necessary, to
maintain weight within ±1 kg. All diets provided the following: 45%
of total calories as carbohydrate, 20% as protein, and 35% as fat;
300 mg cholesterol per day; and no alcohol. The majority of
fat energy at each meal was provided by a single food item made with
vegetable oils that contained no added vitamin E (Hain). Diets were
modified in 3 sequential phases; each phase was 3 weeks long. In phase
1, the major fat source was olive oil. In this diet, 7.5% of the total
calories came from saturated fat; 20%, from MUFA; and 7.5%, from
PUFA. In phase 2, the major fat source was high linoleic safflower oil.
In this diet 7.5% of the total calories came from saturated fat;
7.5%, from MUFA; and 20%, from PUFA. Phase 3 continued the phase 2
diet with the addition of a 400 IU
DL-
-tocopheryl acetate
soft-gel (Eckerd Drug Co) at lunch and dinner.
Measurement of Plasma Lipids, Lipoproteins,
Cotinine, and F2-Isoprostanes
Venous blood was collected in sodium EDTA Vacutainers
after an overnight fast, kept on ice, and centrifuged at 4°C.
Plasma for lipid analysis was stored at 4°C under argon and
assayed within 24 hours for total, LDL, and HDL cholesterol
by a Technicon RA-1000 analyzer. Plasma for isoprostanoid
measurements was stored at -70°C under argon and assayed within 1
week of collection. Plasma total F2-isoprostanes
and prostaglandin F2
(PGF2
) were quantified as
pentafluorobenzyltrimethylsilyl ether derivatives by gas
chromatographymass
spectroscopy,43 with
D4-PGF2
(Cayman Chemical Co) used as an internal standard. Plasma cotinine was
measured by
radioimmunoassay.45
Preparative Isolation of Plasma LDL
Fasting venous blood was collected into 3 mmol/L
sodium EDTA, pH 7.4, 1.5 mmol/L sodium azide, 0.175 mmol/L
gentamicin SO4, and 0.25 mmol/L
chloramphenicol. Plasma was made to 1 mmol/L with benzamidine and
phenylmethylsulfonyl fluoride. LDL was isolated by
ultracentrifugation at 4°C at in a density range of
1.006 to 1.063 g/mL, stored at 4°C in the dark under nitrogen, and
studied within 48 hours. Protein concentration was determined by using
bicinchoninic acid46 with BSA
used as a standard.
Measurement of LDL Fatty Acid and
-Tocopherol Concentration
The fatty acid composition of LDL was determined by
gas chromatography with pentadecanoic acid used as an
internal standard.47 The
-tocopherol concentration in plasma and LDL was measured
by high-pressure liquid chromatography with tocol used
as an internal
standard.48
Measurement of LDL Oxidation Kinetics
LDL oxidation was measured at the end of each phase
by fluorescence
spectroscopy.49 Immediately
before each assay, LDL was dialyzed against PBS, pH 7.4, at 4°C and
diluted to 0.2 g/L. LDL was incubated at 37°C with 200 µmol/L
CuSO4, and the fluorescence intensity at
435 nm was monitored with excitation at 370 nm. Oxidation lag time was
determined at the intercept of the linear segments of the initial lag
phase and the propagation phase; oxidation rate was calculated from the
slope of the propagation curve. Coefficients of variation were as
follows: for lag time, intra-assay 3.5%, interassay 4.4%; for
oxidation rate, intra-assay 7.5%, interassay
7.4%.
Statistical Analysis
The significance of differences in plasma lipoprotein
cholesterol and total vitamin E, LDL fatty acid and vitamin
E composition, LDL oxidation parameters, and plasma
F2-isoprostanes across the 3 diet phases was
determined by 1-way repeated-measures ANOVA with Tukey post hoc
testing. The significance of relationships among parameters
was determined by linear correlation
analysis.
| Results |
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After 3 weeks on the PUFA diet, mean plasma total, LDL, and
HDL cholesterol decreased
(Table 1
), consistent with the well-known effects of
PUFA on plasma
lipoproteins.24 There was no
change in mean plasma
(Table 1
) or LDL
(Table 2
) vitamin E concentration. The mole fraction of
linoleic acid in LDL increased with a reciprocal decrease in oleic
acid; the mole fraction of palmitic acid also increased
(Figure 1
). There was no significant change in LDL
arachidonate content
(Table 2
). The PUFA diet had no impact on LDL oxidation lag
time or rate
(Table 2
). However, mean plasma total
F2-isoprostane concentration increased >2-fold,
and plasma PGF2
concentration increased by
58%
(Table 3
), suggesting that the increase in dietary PUFA had
promoted in vivo free radical oxidation reactions.
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Addition of 800 IU vitamin E per day to the PUFA diet
resulted in no change in plasma lipoprotein levels, in keeping with
previous observations,50 or
in LDL fatty acid composition. However, mean plasma vitamin E
concentration and mean LDL molar vitamin E content increased
significantly
(Tables 1
and 2
). Mean LDL oxidation lag time increased,
reflecting the increase in LDL antioxidant
content,28 38 40
but there was no change in the mean LDL oxidation rate. Nonetheless,
mean plasma total F2-isoprostane and
PGF2
levels increased further by 62% and
47%, respectively, suggesting that vitamin E had a pro-oxidant effect
in the setting of a high PUFA intake.
PGF2
may be formed either
enzymically or by free radical oxidation of arachidonic
acid.43 44 In each
diet phase, there was a tight linear relationship between plasma
concentrations of total F2-isoprostanes and
PGF2
(Figure 2
), suggesting that PGF2
was derived from lipid oxidation. A plot of plasma
F2-isoprostane levels, normalized by the mole
fraction of LDL arachidonate, versus total plasma vitamin E
concentration gave a linear correlation, with
r=0.84 and
P<0.001
(Figure 3
), further suggesting that isoprostane synthesis was
related to vitamin E availability.
|
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| Discussion |
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-tocopherol from tocopheryl
radicals.30 32 34
These conditions may exist in cigarette smokers. The finding that
vitamin E increased total plasma F2 isoprostanes
and PGF2
in smokers consuming a high PUFA
diet suggests that in this setting, vitamin E can function as a
pro-oxidant in vivo. Moreover, the correlation between plasma total
F2 isoprostanes and vitamin E concentration
suggests that the rise in plasma isoprostane levels may have been a
global tissue response to increased vitamin E availability. Mean plasma F2-isoprostane concentration nearly doubled on the PUFA diet, despite the fact that (as reflected by LDL fatty acid composition) there was no change in dietary arachidonate intake. This suggests that dietary arachidonate did not serve as a substrate for increased isoprostane production. Rather, the high PUFA diet, by increasing the intake of oxidizable linoleate, may have increased the flux of free radicals available to initiate isoprostane synthesis from arachidonate already present in peripheral tissues. Alternatively, incorporation of dietary linoleate into cell membranes may have created a more fluid lipid microenvironment that promoted faster diffusion of free radicals. In either case, with the addition of vitamin E to the PUFA diet, the increased tissue availability of vitamin E, functioning in a pro-oxidant mode, may have further enhanced the synthesis of F2-isoprostanes.
Although some studies in smokers have found that vitamin E
decreases breath pentane
excretion18 and
plasma15 16 or red
blood cell17 TBARS, other
studies have noted no effect of vitamin E, or antioxidant cocktails
containing vitamin E, on breath alkane
excretion,51 plasma
TBARS,14 LDL oxidation
rate,27 urinary
8-oxo-PGF2
excretion,52 53
plasma oxysterols,16 or
plasma F2-isoprostane
concentration.54 The
disparities among these studies and our present observations may
reflect a sensitivity of oxidation status in smokers to factors such as
the intensity of smoking, the source and dose of vitamin E, the plasma
concentration of co-antioxidants such as ascorbate, and dietary fatty
acid intake. In this regard, it is important to note that no other
study has used an experimental diet with a PUFA content as high as we
provided in the present study.
In vitro determination of LDL oxidation kinetics has been widely used as a measure of lipoprotein oxidation susceptibility and of the in vivo efficacy of antioxidants.7 37 38 39 40 41 42 However, given the presence of potent aqueous phase antioxidants such as urate and ascorbate,55 it seems unlikely that LDL oxidation could occur in the plasma or interstitial compartments. Moreover, the radical flux rate in vivo is likely orders of magnitude smaller than that generated by chemical catalysis in vitro. Furthermore, in vitro copper-catalyzed oxidation is highly sensitive to the copper/LDL ratio,56 so that very different oxidation kinetics can be obtained depending on the conditions selected.56 57 Therefore, our observation that vitamin E raised plasma F2-isoprostane levels despite prolonging LDL lag time suggests that ex vivo measurement of LDL oxidation may not provide a physiologically relevant measure of global oxidation status.
Whereas some studies have noted that PUFAs alter LDL oxidation kinetics,26 27 39 we, like others,42 58 noted no effect of increasing dietary PUFA on LDL oxidation rate. Similarly, although studies in nonsmokers have noted a salutary effect of vitamin E on LDL kinetic parameters,38 41 we noted no effect of vitamin E on the mean LDL oxidation rate. Again, these disparities may be a function of the specific conditions of each study. Indeed, because copper-catalyzed oxidation is sensitive to the number of copper-binding sites on the LDL surface59 and LDL phospholipid fatty acid composition,60 the large interindividual variability in these factors27 57 60 will tend to obscure all but the largest differences in oxidation kinetics among different studies.
There are several important caveats to the present study. First, we did not evaluate the effect of vitamin E on lipid oxidation on the MUFA diet, so we cannot determine whether its pro-oxidant effect in smokers was a unique consequence of its coadministration with a high-PUFA diet. However, because there appears to be no synergistic antioxidant effect of vitamin E supplementation and a high MUFA intake,39 40 we believe that vitamin E would be less likely to function as a pro-oxidant in this setting. Second, we did not conduct parallel studies in nonsmokers, so we cannot conclude that vitamin E acts as a pro-oxidant exclusively in smokers consuming a high PUFA diet. Finally, the copper/LDL molar ratio we used in our in vitro oxidation assay (500:1) is higher than that used in other studies, and as noted above, oxidation kinetics are highly sensitive to the copper/LDL ratio.56
In summary, our data suggest that supplementing cigarette smokers with vitamin E, in the setting of a high PUFA diet, promotes in vivo lipid oxidation, as evidenced by increased plasma F2-isoprostane levels. Even though it is unlikely that many smokers would consume a diet containing the high content of PUFA that we used in the present study, because F2-isoprostanes are vasoactive and increase platelet activation,43 44 our findings suggest caution in the use of high-dose vitamin E supplementation as a therapeutic means to reduce the risk of ASCVD in cigarette smokers.
| Acknowledgments |
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| Footnotes |
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Received January 5, 2001; accepted March 20, 2001.
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R. M. Salonen, K. Nyyssonen, J. Kaikkonen, E. Porkkala-Sarataho, S. Voutilainen, T. H. Rissanen, T.-P. Tuomainen, V.-P. Valkonen, U. Ristonmaa, H.-M. Lakka, et al. Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study Circulation, February 25, 2003; 107(7): 947 - 953. [Abstract] [Full Text] [PDF] |
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D. C. Schwenke, L. L. Rudel, M. G. Sorci-Thomas, and M. J. Thomas {alpha}-Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits J. Lipid Res., November 1, 2002; 43(11): 1927 - 1938. [Abstract] [Full Text] [PDF] |
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