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© 1997 American Heart Association, Inc.
Articles |
In Vivo Formation of 8-Epi-Prostaglandin F2
Is Increased in Hypercholesterolemia
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
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Abstract |
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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
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 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. 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 on platelet activation.
Urinary 8-epi-PGF2 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 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 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 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 formation
by vitamin E supplementation may contribute to the beneficial effects
of antioxidant treatment.
Key Words: aspirin • F2-isoprostanes • thromboxane • hypercholesterolemia • vitamin E
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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, 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 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 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.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 1
. 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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Design of the Studies
In the first study, a cross-sectional comparison of urinary
8-epi-PGF2 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 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 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--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 and
11-dehydro-TXB2 were measured by previously described and
validated radioimmunoassay methods.14 25 For
8-epi-PGF2 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 serum has been described
previously.14 Measurements of urinary
8-epi-PGF2 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).
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Urinary excretion of the F2-isoprostane 8-epi-PGF2
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 1). In patients, this biochemical index
of in vivo lipid peroxidation was directly correlated with
LDL-cholesterol levels (
=.386, P=.0159) and
inversely related to the vitamin E content of LDL (=-.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 2, a statistically significant
correlation was found between the rates of excretion of
8-epi-PGF2 and 11-dehydro-TXB2,
suggesting a potential link between lipid peroxidation and platelet
activation.
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Effects of Aspirin and Indobufen
To verify whether enhanced 8-epi-PGF2
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
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 3.
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Besides demonstrating that 8-epi-PGF2 was
produced independently of cyclooxygenase activity,
this study also provided an opportunity to assess the reproducibility
of urinary 8-epi-PGF2 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 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 4, vitamin E supplementation was
associated with a statistically significant (P<.001),
dose-dependent reduction in urinary
8-epi-PGF2 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
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
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 5).
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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 2). In these 22
hypercholesterolemic patients, urinary excretion of
8-epi-PGF2 was inversely related to vitamin
E levels in both plasma and LDL (Fig 6)
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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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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 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 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 was abnormally
elevated in the vast majority of hypercholesterolemic
patients. Inasmuch as a minor component of
8-epi-PGF2 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 biosynthesis in
hypercholesterolemia. Within the limitations of
the relatively small sample size, the finding of unchanged excretion of
8-epi-PGF2, 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 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
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 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 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 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 excretion,
based on the linear correlation between the two, was actually observed
after suppressing 8-epi-PGF2 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 -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.
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Acknowledgments |
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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.
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Footnotes |
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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.
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G. CIABATTONI, G. DAVI, M. COLLURA, L. IAPICHINO, F. PARDO, A. GANCI, R. ROMAGNOLI, J. MACLOUF, and C. PATRONO In Vivo Lipid Peroxidation and Platelet Activation in Cystic Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1195 - 1201. [Abstract] [Full Text] [PDF]
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E. Porkkala-Sarataho, J. T. Salonen, K. Nyyssonen, J. Kaikkonen, R. Salonen, U. Ristonmaa, U. Diczfalusy, R. Brigelius-Flohe, S. Loft, and H. E. Poulsen 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 Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2087 - 2093. [Abstract] [Full Text] [PDF]
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F. Cipollone, G. Ciabattoni, P. Patrignani, M. Pasquale, D. Di Gregorio, T. Bucciarelli, G. Davi, F. Cuccurullo, and C. Patrono Oxidant Stress and Aspirin-Insensitive Thromboxane Biosynthesis in Severe Unstable Angina Circulation, August 29, 2000; 102(9): 1007 - 1013. [Abstract] [Full Text] [PDF]
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O. Belton, D. Byrne, D. Kearney, A. Leahy, and D. J. Fitzgerald Cyclooxygenase-1 and -2-Dependent Prostacyclin Formation in Patients With Atherosclerosis Circulation, August 22, 2000; 102(8): 840 - 845. [Abstract] [Full Text] [PDF]
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B. Halliwell Lipid peroxidation, antioxidants and cardiovascular disease: how should we move forward? Cardiovasc Res, August 18, 2000; 47(3): 410 - 418. [Full Text] [PDF]
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A. Mezzetti, F. Cipollone, and F. Cuccurullo Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm Cardiovasc Res, August 18, 2000; 47(3): 475 - 488. [Abstract] [Full Text] [PDF]
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H. Wiseman, J. D O'Reilly, H. Adlercreutz, A. I Mallet, E. A Bowey, I. R Rowland, and T. A. Sanders Isoflavone phytoestrogens consumed in soy decrease F2-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans Am. J. Clinical Nutrition, August 1, 2000; 72(2): 395 - 400. [Abstract] [Full Text] [PDF]
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P. Patrignani, M. R. Panara, S. Tacconelli, F. Seta, T. Bucciarelli, G. Ciabattoni, P. Alessandrini, A. Mezzetti, G. Santini, M. G. Sciulli, et al. Effects of Vitamin E Supplementation on F2-Isoprostane and Thromboxane Biosynthesis in Healthy Cigarette Smokers Circulation, August 1, 2000; 102(5): 539 - 545. [Abstract] [Full Text] [PDF]
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 M. Schwemmer, O. Sommer, R. Koeckerbauer, and E. Bassenge Cardiovascular Dysfunction in Hypercholesterolemia Associated With Enhanced Formation of ATI-Receptor and of Eicosanoids Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(1): 59 - 68. [Abstract] [PDF]
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E. Södergren, J. Cederberg, S. Basu, and B. Vessby Vitamin E Supplementation Decreases Basal Levels of F2-Isoprostanes and Prostaglandin F2{alpha} in Rats J. Nutr., January 1, 2000; 130(1): 10 - 14. [Abstract] [Full Text]
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C. Palombo, V. Lubrano, and T. Sampietro Oxidative stress, F2-isoprostanes and endothelial dysfunction in hypercholesterolemia Cardiovasc Res, December 1, 1999; 44(3): 474 - 476. [Full Text] [PDF]
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S. H. Wilson, P. J.M. Best, L. O. Lerman, D. R. Holmes Jr., D. M. Richardson, and A. Lerman Enhanced coronary vasoconstriction to oxidative stress product, 8-epi-prostaglandinF2{alpha}, in experimental hypercholesterolemia Cardiovasc Res, December 1, 1999; 44(3): 601 - 607. [Abstract] [Full Text] [PDF]
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P. J. M. Best, L. O. Lerman, J. C. Romero, D. Richardson, D. R. Holmes Jr, and A. Lerman Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2769 - 2775. [Abstract] [Full Text] [PDF]
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P. Pignatelli, F. M. Pulcinelli, L. Lenti, P. P. Gazzaniga, and F. Violi Vitamin E Inhibits Collagen-Induced Platelet Activation by Blunting Hydrogen Peroxide Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2542 - 2547. [Abstract] [Full Text] [PDF]
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 A. D. Watson, G. Subbanagounder, D. S. Welsbie, K. F. Faull, M. Navab, M. E. Jung, A. M. Fogelman, and J. A. Berliner Structural Identification of a Novel Pro-inflammatory Epoxyisoprostane Phospholipid in Mildly Oxidized Low Density Lipoprotein J. Biol. Chem., August 27, 1999; 274(35): 24787 - 24798. [Abstract] [Full Text] [PDF]
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M. Reza Mehrabi, C. Ekmekcioglu, F. Tatzber, A. Oguogho, R. Ullrich, A. Morgan, F. Tamaddon, M. Grimm, H. D Glogar, and H. Sinzinger The isoprostane, 8-epi-PGF2{alpha}, is accumulated in coronary arteries isolated from patients with coronary heart disease Cardiovasc Res, August 1, 1999; 43(2): 492 - 499. [Abstract] [Full Text] [PDF]
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R. BRIGELIUS-FLOHÉ and M. G. TRABER Vitamin E: function and metabolism FASEB J, July 1, 1999; 13(10): 1145 - 1155. [Abstract] [Full Text]
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A. C Carr and B. Frei Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans Am. J. Clinical Nutrition, June 1, 1999; 69(6): 1086 - 1107. [Abstract] [Full Text] [PDF]
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G. Davi, G. Ciabattoni, A. Consoli, A. Mezzetti, A. Falco, S. Santarone, E. Pennese, E. Vitacolonna, T. Bucciarelli, F. Costantini, et al. In Vivo Formation of 8-Iso-Prostaglandin F2{alpha} and Platelet Activation in Diabetes Mellitus : Effects of Improved Metabolic Control and Vitamin E Supplementation Circulation, January 19, 1999; 99(2): 224 - 229. [Abstract] [Full Text] [PDF]
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J. L. Witztum To E or Not To E—How Do We Tell? Circulation, December 22, 1998; 98(25): 2785 - 2787. [Full Text] [PDF]
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M. P. Reilly, D. Pratico, N. Delanty, G. DiMinno, E. Tremoli, D. Rader, S. Kapoor, J. Rokach, J. Lawson, and G. A. FitzGerald Increased Formation of Distinct F2 Isoprostanes in Hypercholesterolemia Circulation, December 22, 1998; 98(25): 2822 - 2828. [Abstract] [Full Text] [PDF]
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J. A. Lawson, H. Li, J. Rokach, M. Adiyaman, S.-W. Hwang, S. P. Khanapure, and G. A. FitzGerald Identification of Two Major F2 Isoprostanes, 8,12-Iso- and 5-epi-8,12-Iso-isoprostane F2alpha -VI, in Human Urine J. Biol. Chem., November 6, 1998; 273(45): 29295 - 29301. [Abstract] [Full Text] [PDF]
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G. Davi, M. Romano, A. Mezzetti, A. Procopio, S. Iacobelli, T. Antidormi, T. Bucciarelli, P. Alessandrini, F. Cuccurullo, and G. B. Bon Increased Levels of Soluble P-Selectin in Hypercholesterolemic Patients Circulation, March 17, 1998; 97(10): 953 - 957. [Abstract] [Full Text] [PDF]
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 M. A. Forgione, N. Weiss, S. Heydrick, A. Cap, E. S. Klings, C. Bierl, R. T. Eberhardt, H. W. Farber, and J. Loscalzo Cellular glutathione peroxidase deficiency and endothelial dysfunction Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1255 - H1261. [Abstract] [Full Text] [PDF]
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