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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3230-3235

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Articles

In Vivo Formation of 8-Epi-Prostaglandin F2{alpha} Is Increased in Hypercholesterolemia

Giovanni Davi; Paola Alessandrini; Andrea Mezzetti; Giorgio Minotti; Tonino Bucciarelli; Fabrizio Costantini; Francesco Cipollone; Gabriele Bittolo Bon; Giovanni Ciabattoni; ; Carlo Patrono

From the Departments of Medicine (G.D. A.M., F. Costantini, F. Cipollone), Pharmacology (C.P.), and Biochemistry (T.B.), University of Chieti "G. D'Annunzio" School of Medicine, Chieti; the Department of Pharmacology, Catholic University School of Medicine, Rome (G.M., G.C.); and the Division of Internal Medicine, Civil Hospital of Venice (P.A., G.B.B.), Italy.

Correspondence to Carlo Patrono, MD, Cattedra di Farmacologia I, Universita degli Studi "G. D'Annunzio," Via del Vestini 31, 66013 Chieti, Italy. E-mail cpatrono{at}unich.it


*    Abstract
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*Abstract
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down arrowMethods
down arrowResults
down arrowDiscussion
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Abstract F2-isoprostanes are bioactive prostaglandin (PG) -like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2{alpha} may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2{alpha} is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2{alpha}. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2{alpha} on platelet activation. Urinary 8-epi-PGF2{alpha} was significantly (P=.0001) higher in hypercholesterolemic patients than in control subjects: 473±305 versus 205±95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2{alpha} was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2{alpha} and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F2-isoprostane 8-epi-PGF2{alpha} is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2{alpha} formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.


Key Words: aspirin • F2-isoprostanes • thromboxane • hypercholesterolemia • vitamin E


*    Introduction
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up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
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High cholesterol levels have an established role in the development of atherosclerotic vascular lesions and in cardiovascular events induced by vascular occlusion.1 Evidence for this role has been inferred from both epidemiological and intervention studies.2 3 However, occlusive events may occur in the absence of grossly elevated cholesterol levels, particularly when other risk factors, such as cigarette smoking, diabetes mellitus, and hypertension, are present. A link between moderately elevated cholesterol levels and other risk factors for cardiovascular disease has been proposed to involve oxidative modifications of LDL.4 Oxidatively modified LDL has been found in foam cells and atherosclerotic plaques and has been shown to acquire a variety of properties that may be relevant to the process of atherogenesis.4 5 Moreover, an increased susceptibility of LDL to in vitro oxidation has been demonstrated in hypercholesterolemic patients.6 7

Recently a series of bioactive prostaglandin (PG) F2-like compounds (isoprostanes) has been discovered,8 which are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation, catalyzed by oxygen free radicals on cell membranes9 and LDL particles.10 Among these products of particular importance is 8-epi-PGF2{alpha}, which induces vasoconstriction11 and modulates the function of human platelets.12 13 F2-isoprostanes can be reliably measured in both plasma and urine9 and have been shown to be increased in association with advanced age,14 diabetes mellitus,15 and cigarette smoking.16 17 These findings suggest that quantification of these prostanoids may provide a novel approach to the assessment of oxidant injury in humans.8 9 10

In the present study, we set out to investigate whether urinary excretion of 8-epi-PGF2{alpha} was increased in patients with hypercholesterolemia when compared with sex- and age-matched normocholesterolemic subjects. Moreover, we investigated the mechanism of the increased formation of F2-isoprostanes by means of cyclooxygenase inhibitors and vitamin E supplementation. Finally, we examined the relationship between the rates of excretion of 8-epi-PGF2{alpha} and 11-dehydro-thromboxane (TX) B2, a noninvasive index of in vivo platelet activation. The results suggest a biochemical link between lipid peroxidation and platelet activation and provide a rationale for further studies of vitamin E supplementation in hypercholesterolemia.


*    Methods
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up arrowIntroduction
*Methods
down arrowResults
down arrowDiscussion
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Subjects
Forty hypercholesterolemic patients (31 women and 9 men, aged 55±8 years; mean±SD) and 40 sex- and age-matched normocholesterolemic subjects attending the Lipid Clinics of Venice General Hospital and of the University of Chieti School of Medicine were asked to participate in the study. Most of the hyperlipidemic patients had been followed up by the two clinics for several years. LDL cholesterol levels for inclusion in the study as a hypercholesterolemic subject were >=180 mg/dL. Two patients were also included, despite the fact that their LDL cholesterol levels at the time of study were 160 mg/dL because of numerous prior measurements that had been >=180 mg/dL. None of the participating subjects were taking any drugs, vitamins, or dietary supplements. The hypercholesterolemic patients were not taking lipid-lowering drugs because either they were unwilling to do so or they were still on a diet before drug treatment. None of the patients had clinical evidence of cardiovascular disease (by clinical history, physical examination, and ECG). Patients with renal insufficiency or proteinuria (by serum creatinine levels and urinalysis), altered hepatic function (by liver enzymes), diabetes mellitus, or alcohol abuse were excluded. None of the subjects was a smoker at the time of study. All patients had been on an American Heart Association step 1 diet for at least 2 months before the study. All of the patients and control subjects were studied between March 1995 and January 1996. The study was approved by the local Ethics Committees, and all patients gave their written informed consent to participate in the study.

The plasma lipid profile of patients and control subjects is reported in Table 1Down. Thirty-eight of the 40 patients were phenotype IIA according to the World Health Organization classification; the remaining two were classified as type IIB, although they had been characterized as IIA during most of their previous clinic visits.


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Table 1. Plasma Lipid Levels in Hypercholesterolemic Patients and in Age- and Sex-Matched Control Subjects

Design of the Studies
In the first study, a cross-sectional comparison of urinary 8-epi-PGF2{alpha} and 11-dehydro-TXB2 (a major enzymatic metabolite of TXA2) was performed between patients and control subjects. All subjects were studied as outpatients after a 12-hour fast. Blood samples were obtained for the following measurements: total cholesterol, triglycerides, HDL cholesterol, plasma and LDL vitamin E levels, oxidation of isolated LDL, and the necessary parameters to verify inclusion/exclusion criteria. Each patient performed two 12-hour overnight urine collections, one immediately before blood sampling and the other 48 hours afterward. Urine samples were supplemented with the antioxidant 4-hydroxy-tempo (1 mmol/L) and stored at -20°C until extraction.

A second study was performed to evaluate whether the inhibition of cyclooxygenase activity had any influence on 8-epi-PGF2{alpha} excretion. For this purpose, 6 of the 40 patients were given 50 mg acetylsalycilic acid once daily and 200 mg indobufen (a reversible cyclooxygenase inhibitor) twice daily for 7 days in successive weeks according to a randomized sequence. From these patients, 12-hour overnight urine samples were collected on the 2 consecutive days before dosing and on the last 2 days of each treatment.

To investigate the short-term effects of an antioxidant on urinary 8-epi-PGF2{alpha} and 11-dehydro-TXB2 excretion, vitamin E was given to 22 (16 women and 6 men; aged 56±7 years; mean±SD) of the 40 hypercholesterolemic patients. They were given 100 mg d,l-{alpha}-tocopherol acetate (Evion) daily for 2 weeks after their baseline evaluation. On the 14th day, these patients returned to the clinic with a 12-hour overnight urine sample and had a fasting blood sample drawn for lipid levels, plasma and LDL vitamin E levels, and oxidation of isolated LDL. A second 12-hour urine collection during vitamin E (100 mg) administration was obtained 24 hours later. Thereafter the patients took 600 mg/d of the same formulation of vitamin E for 2 weeks and repeated the same urine collection and blood sampling as with the 100-mg dose.

Lipid Measurements
All blood samples for lipid studies were drawn into EDTA-(1 mg/mL) containing tubes and separated within 1 hour after sampling. Total cholesterol and triglyceride levels were determined by an enzymatic method, and the HDL cholesterol level was measured after phosphotungstic acid/MgCl2 precipitation of fresh plasma. LDL cholesterol was calculated by the formula of Friedewald et al.18 Immediately after separation, aliquots of the plasma in EDTA were stored at -80°C until LDL isolation. Previous studies have shown that plasma storage and freezing/thawing does not affect LDL isolation or its major chemical characteristics.19 LDL was isolated by single vertical-spin density gradient ultracentrifugation.20 21 After dialysis against PBS, pH 7.4, at 4°C, LDL protein, cholesterol, and vitamin E levels were determined by established methods.22 23 To induce oxidation, LDL (0.2 mg cholesterol per milliliter) was incubated with 5 µmol/L CuSO4 in PBS, pH 7.4, at 37°C. Formation of conjugated dienes was then determined spectrophotometrically by monitoring the increase in absorbance at 234 nm.24 Vitamin E plasma content was determined by high-performance liquid chromatography.23

Urinary Eicosanoid Assays
Urinary 8-epi-PGF2{alpha} and 11-dehydro-TXB2 were measured by previously described and validated radioimmunoassay methods.14 25 For 8-epi-PGF2{alpha} measurement, 10-mL urine aliquots were extracted on Sep-Pak C18 cartridges (Waters Associates) after adjusting the pH to 4 with formic acid and eluted with 10 mL ethyl acetate. The eluates were subjected to silicic acid chromatography and further eluted with benzene/ethyl acetate/methanol (60:40:30, vol/vol/vol). These eluates were dried, recovered with 5 mL of buffer, and assayed in the radioimmunoassay system at a final dilution ranging between 1:30 and 1:60. The specificity of the anti–8-epi-PGF2{alpha} serum has been described previously.14 Measurements of urinary 8-epi-PGF2{alpha} by this radioimmunoassay have been validated using different antisera and by comparison with gas chromatography/mass spectrometry, as detailed elsewhere.14

Statistical Analysis
The data were analyzed by nonparametric methods to avoid assumptions about the distribution of the measured variables. An ANOVA was performed with the Kruskal-Wallis method. Subsequent pairwise comparisons were made with the Mann-Whitney U test. The differences between baseline and posttreatment values were analyzed with the Wilcoxon signed-rank test. Moreover, the association of eicosanoid measurements with other biochemical parameters was assessed by the Spearman rank correlation test. All values are reported as mean±SD. Statistical significance was considered to be indicated by a value of P<.05. All calculations were made with the computer program Stat View (Abacus Concepts).


*    Results
up arrowTop
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up arrowMethods
*Results
down arrowDiscussion
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Urinary excretion of the F2-isoprostane 8-epi-PGF2{alpha} was significantly (P=.0001) higher in hypercholesterolemic patients than in age- and sex-matched control subjects: 473±305 versus 208±95 pg/mg creatinine (Fig 1Down). In patients, this biochemical index of in vivo lipid peroxidation was directly correlated with LDL-cholesterol levels ({rho}=.386, P=.0159) and inversely related to the vitamin E content of LDL ({rho}=-.539, P=.0051). Consistent with previous findings,26 hypercholesterolemic patients had a significantly (P=.0001) higher excretion rate of 11-dehydro-TXB2, an index of in vivo platelet activation, than did control subjects: 1152±687 versus 319±164 pg/mg creatinine, respectively. As depicted in Fig 2Down, a statistically significant correlation was found between the rates of excretion of 8-epi-PGF2{alpha} and 11-dehydro-TXB2, suggesting a potential link between lipid peroxidation and platelet activation.



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Figure 1. Urinary excretion of 8-epi-PG F2{alpha} in patients with hypercholesterolemia and in healthy subjects. The dots representing hypercholesterolemic patients are connected to a dot representing a healthy subject matched to the patient for age and sex. Each dot represents the average of two consecutive measurements.



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Figure 2. Correlation between urinary excretion rates of 8-epi-PGF2{alpha} and 11-dehydro-TXB2 in 40 hypercholesterolemic patients.

Effects of Aspirin and Indobufen
To verify whether enhanced 8-epi-PGF2{alpha} excretion reflected a noncyclooxygenase mechanism of F2-isoprostane biosynthesis, we used two structurally unrelated cyclooxygenase inhibitors, aspirin and indobufen. When given to 6 hypercholesterolemic patients (each drug for 7 days in 2 successive weeks), this pharmacological treatment produced no detectable changes in urinary 8-epi-PGF2{alpha} excretion, though completely suppressing 11-dehydro-TXB2 excretion. Because the randomized sequence of treatment had no detectable influence on the pattern of eicosanoid excretion, the results obtained for the 6 patients were combined, as depicted in Fig 3Down.



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Figure 3. Urinary excretion of 8-epi-PGF2{alpha} (upper panel) and 11-dehydro-TXB2 (lower panel) before and after cyclooxygenase inhibition with aspirin and indobufen. Eicosanoid levels were measured in 6 hypercholesterolemic patients on 2 consecutive days before dosing and on the last 2 days of each week of consecutive treatment with either aspirin (50 mg daily) or indobufen (200 mg twice daily). Cyclooxygenase inhibition, as reflected by the statistically significant (P<.03) suppression of TX biosynthesis, produced no detectable changes in urinary 8-epi-PGF2{alpha} excretion.

Besides demonstrating that 8-epi-PGF2{alpha} was produced independently of cyclooxygenase activity, this study also provided an opportunity to assess the reproducibility of urinary 8-epi-PGF2{alpha} excretion upon repeated sampling. Based on six determinations over a 3-week period, the intrasubject coefficient of variation of this index averaged 20±9%.

Effects of Vitamin E
We next examined the effects of vitamin E supplementation on the urinary excretion of 8-epi-PGF2{alpha} and 11-dehydro-TXB2 to test the hypothesis of a cause-effect relationship between enhanced lipid peroxidation and platelet activation. Thus, we measured the effects of vitamin E (100 and 600 mg daily); each dose given was for 14 days in successive weeks to 22 of the 40 hypercholesterolemic patients. As shown in Fig 4Down, vitamin E supplementation was associated with a statistically significant (P<.001), dose-dependent reduction in urinary 8-epi-PGF2{alpha} excretion by 34% and 58% at the 100- and 600-mg dose, respectively. During supplementation with 600 mg vitamin E daily, urinary 8-epi-PGF2{alpha} excretion averaged 187±66 pg/mg creatinine, and all individual values fell within the range of those of the control subjects. These changes in 8-epi-PGF2{alpha} formation were also associated with a statistically significant (P<.001), dose-dependent reduction in urinary 11-dehydro-TXB2 excretion by 36% and 47% at the 100- and 600-mg dose, respectively. A statistically significant correlation was found between the rates of excretion of these eicosanoids throughout the range of values measured at baseline and after 100 and 600 mg of vitamin E supplementation (Fig 5Down).



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Figure 4. Effects of vitamin E supplementation on urinary excretion of 8-epi-PGF2{alpha} (upper panel) and 11-dehydro-TXB2 (lower panel) in hypercholesterolemic patients. Eicosanoid levels were measured in 22 hypercholesterolemic patients twice before starting supplementation (baseline), on 2 consecutive days at the end of a 2-week daily dosing with 100 mg vitamin E, and on 2 consecutive days at the end of a 2-week daily dosing with 600 mg vitamin E. Solid bars depict mean±SD values for the whole group of patients. P<.001 for comparison of the 100- or 600-mg dose vs baseline for both eicosanoids.



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Figure 5. Correlation between the urinary excretion rates of 8-epi-PGF2{alpha} and 11-dehydro-TXB2. Sixty-six paired measurements were obtained from 22 hypercholesterolemic patients: before vitamin E supplementation and at the end of the two 2-week treatment periods with 100 mg and 600 mg daily.

Vitamin E supplementation was also associated with statistically significant increases in plasma vitamin E levels, vitamin E content of LDL, and lag-time for LDL oxidation (Table 2Down). In these 22 hypercholesterolemic patients, urinary excretion of 8-epi-PGF2{alpha} was inversely related to vitamin E levels in both plasma and LDL (Fig 6Down) and to the lag-time for LDL oxidation (data not shown). No statistically significant changes in blood lipid levels were measured during vitamin E supplementation.


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Table 2. Concentrations of Vitamin E in Plasma, Vitamin E Content of LDL, and Lag Time for LDL Oxidation in Hypercholesterolemic Patients on Vitamin E Supplementation



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Figure 6. Correlation between urinary 8-epi-PGF2{alpha} levels and concentration of vitamin E in plasma (upper panel) and in LDL (lower panel). Sixty-six paired measurements were obtained from 22 hypercholesterolemic patients: before vitamin E supplementation and at the end of the two 2-week treatment periods with 100 mg and 600 mg daily.


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Oxygen free-radical reactions have been implicated in many chronic disease processes, including cardiovascular disease. Moreover, there is increasing experimental and epidemiological evidence that oxidative modifications of LDL play an important role in the development of atherosclerotic lesions.4 5 27

Previous evidence for enhanced lipid peroxidation in hypercholesterolemic patients is fairly indirect and based on crude measurements of lipid oxidation products in plasma or the susceptibility of the patient's LDL to oxidation in vitro.6 7 Our study has used the urinary excretion of the F2-isoprostane 8-epi-PGF2{alpha} as a marker of in vivo lipid peroxidation.8 9 Measurement of this compound has several distinct advantages over other methods:(1) It reflects a nonenzymatic process of lipid peroxidation of a ubiquitous, endogenous substrate, ie, arachidonic acid, that is catalyzed by oxygen radicals.8 (2) Once released from cell membranes or circulating LDL, 8-epi-PGF2{alpha} circulates in the plasma.9 and (3) Urinary excretion of this metabolite has been well characterized in humans.9 14 This analytical approach has been previously used to demonstrate enhanced lipid peroxidation in association with advanced age,14 diabetes mellitus,15 and cigarette smoking.16 17

In the present study, we found that the formation and urinary excretion of 8-epi-PGF2{alpha} was abnormally elevated in the vast majority of hypercholesterolemic patients. Inasmuch as a minor component of 8-epi-PGF2{alpha} production can be derived from cyclooxygenase activity of platelet PGH synthase-1 (the constitutive enzyme)28 and of monocyte PGH synthase-2 (the inducible enzyme),29 30 we used low-dose aspirin and indobufen to probe the potential cyclooxygenase dependence of increased 8-epi-PGF2{alpha} biosynthesis in hypercholesterolemia. Within the limitations of the relatively small sample size, the finding of unchanged excretion of 8-epi-PGF2{alpha}, despite virtually complete suppression of TX biosynthesis, demonstrates that this F2-isoprostane is produced in a cyclooxygenase-independent fashion in this setting, consistent with its being a product of lipid peroxidation.8

Vitamin E is a potent, lipid-soluble antioxidant present in LDL, and supplementation with pharmacological doses of vitamin E dose-dependently protects human LDL against oxidative modifications produced in vitro by various procedures.31 32 33 34 35 36 37 The basal rate of 8-epi-PGF2{alpha} biosynthesis was at least in part influenced by the vitamin E content of LDL, as suggested by the inverse correlation between the two. This suggestion is supported by the vitamin E supplementation study, which demonstrates that a dose-dependent reduction in 8-epi-PGF2{alpha} excretion is associated with an increase in the vitamin E content of LDL and its resistance to oxidation in vitro.

Abnormal F2-isoprostane formation was at least in part related to high LDL-cholesterol levels, as suggested by the correlation between the two. Because 8-epi-PGF2{alpha} has biological effects on vascular11 and platelet12 13 38 function, enhanced production of this compound might mediate some of the effects of hypercholesterolemia on important determinants of vascular occlusion. Thus, the ability of 8-epi-PGF2{alpha} to amplify the aggregation response to subthreshold concentrations of platelet agonists such as ADP may be relevant in settings where platelet activation and enhanced lipid peroxidation coincide,38 such as hypercholesterolemia. That increased formation of 8-epi-PGF2{alpha} may have an effect on platelet activation is suggested by the correlation between its basal rate of excretion and the rate of TX biosynthesis. Moreover, the expected change in TX metabolite excretion associated with a 50% to 60% reduction in 8-epi-PGF2{alpha} excretion, based on the linear correlation between the two, was actually observed after suppressing 8-epi-PGF2{alpha} formation by vitamin E supplementation. Although reduced TXA2 biosynthesis may have reflected a direct antiplatelet effect due to vitamin E, this scenario seems unlikely in light of the high-dose requirement (1200 IU/d of {alpha}-tocopherol) for inhibition of arachidonate-induced platelet aggregation ex vivo.39 One potential limitation of the present study is represented by the absence of a functional assessment of platelet reactivity in response to various agonists in vitro. However, it should be pointed out that although platelet aggregation studies may be mechanistically informative, they do not reflect the extent of platelet activation in vivo, inasmuch as the biosynthetic capacity of human platelets to produce TXA2 when challenged in vitro exceeds the actual rate of TXA2 biosynthesis in vivo by several orders of magnitude.40 41

Reduced formation of bioactive isoprostanes might contribute to the beneficial effects of vitamin E supplementation in protecting against cardiovascular events. In patients with angiographically proven coronary atherosclerosis and borderline high blood cholesterol levels who received treatment with an average daily dose of 83 mg aspirin, supplementation with 268 to 537 mg of vitamin E daily reduced the risk of the primary end-point, cardiovascular death and nonfatal myocardial infarction, after a median follow-up time of 1.4 years (relative risk, .53; 95% confidence interval, .34 to .83; P=.005).42 Although several mechanisms might contribute to these effects of pharmacological doses of vitamin E, reduction of an aspirin-insensitive prothrombotic factor is a plausible explanation for the time frame of the observed benefit. Our present findings are consistent with such an interpretation by providing evidence for an aspirin-insensitive mechanism of the amplification of platelet activation, mediated by nonenzymatic peroxidation of arachidonic acid and suppressible by pharmacological doses of vitamin E. There is still uncertainty as to the optimal dose of vitamin E to be tested in long-term intervention studies.43 The results of the present study provide a rationale for dose-ranging studies based on measurements of F2-isoprostane formation in appropriate target populations.


*    Acknowledgments
 
This study was supported by grants from Consiglio Nazionale delle Ricerche (CNR), Progetto Finalizzato Prevenzione e Controllo dei Fattori di Malattia to C.P. and G.D. (SP8: 94.00560.PF41, 94.00627.PF41, 95.00882.PF41, and 95.00807.PF41), and a BIOMED grant from the European Union to C.P. (BMH1-CT93-1533). The expert editorial assistance of Alessandra Migliavacca and Andre Harris is gratefully acknowledged. We also wish to thank Teresa Antidormi, Sandra De Cecco, Domenico De Cesare, Salvatore Roccaforte, and Stella Santarone for assistance with the patients studies.


*    Footnotes
 
Presented in part at the Biomedicine '96 meeting, Washington DC, May 3-6, 1996, and published in abstract form (J Invest Med. 1996;44:224A).

Received December 26, 1996; accepted May 29, 1997.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 
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