(Circulation. 1999;99:224-229.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
In Vivo Formation of 8-Iso-Prostaglandin F2
and Platelet Activation in Diabetes Mellitus
Effects of Improved Metabolic Control and Vitamin E Supplementation
From the Departments of Medicine and Aging (G.D., A.C., A.M., S.S., E.P., E.V., F. Costantini, F. Capani, C.P.) and Biomedical Sciences (T.B.), University of Chieti "G. D'Annunzio" School of Medicine; the Division of Internal Medicine, Civil Hospital of Popoli (A.F.); and the Department of Pharmacology (G.C.), Catholic University School of Medicine; Rome, Italy.
Correspondence to Dr Patrono, Department of Medicine and Aging, University of Chieti "G. D'Annunzio," via dei Vestini 31, 66013 Chieti, Italy. E-mail cpatrono{at}unich.it
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Abstract |
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Background—Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F2-isoprostane 8-iso-prostaglandin (PG)F2
, a bioactive
product of arachidonic acid peroxidation, is
enhanced in DM and contributes to platelet activation.
Methods and Results—Urine samples were obtained from 85 diabetic
patients and 85 age- and sex-matched healthy subjects for measurement
of immunoreactive 8-iso-PGF2 and
11-dehydro-thromboxane B2 (TXM), an in vivo
index of platelet activation. Sixty-two had non–insulin-dependent
(NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E
supplementation, metabolic control, and
cyclooxygenase inhibitors were used to
investigate the mechanisms of formation of 8-iso-PGF2 in
this setting. Urinary 8-iso-PGF2 excretion was
significantly higher (P=0.0001) in NIDDM patients
(419±208 pg/mg creatinine; range 160 to 1014) than in
age-matched control subjects (208±92; 41 to 433). Urinary
8-iso-PGF2 was linearly correlated with blood glucose
and urinary TXM. 8-iso-PGF2 excretion was also
significantly (P=0.0001) higher in IDDM patients
(400±146; 183 to 702) than in control subjects (197±69; 95 to 353).
Vitamin E supplementation (600 mg/d for 14 days) was associated with a
statistically significant reduction in both urinary
8-iso-PGF2 (by 37%) and TXM (by 43%) in 10 NIDDM
patients. Improved metabolic control was associated with a
significant (P=0.0001) reduction in
8-iso-PGF2 and TXM excretion by 32% and 41%,
respectively, in 21 NIDDM patients. 8-iso-PGF2 was
unchanged after 2-week dosing with aspirin and indobufen despite
profound suppression of TXM excretion.
Conclusions—We conclude that DM is associated with increased formation of F2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation. These results provide a rationale for dose-finding studies of antioxidant treatment in diabetes.
Key Words: diabetes mellitus • platelets • lipids • thromboxane • antioxidants
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There is a well-established association of diabetes mellitus with the development of atherosclerosis and its thromboembolic complications and with the occurrence of disorders of the microvasculature.1 However, the mechanism(s) responsible for accelerated atherogenesis remain elusive. Altered lipoprotein levels; changes in lipoprotein composition, possibly affecting low-density lipoprotein (LDL) binding to its receptors; and reduced LDL clearance resulting from impaired receptor recognition of glycated LDL have been described in diabetic patients (reviewed in Reference 22 ). Moreover, both high glucose levels and protein glycation enhance LDL oxidation by metal ions, and these reactions also yield advanced glycosylation end (AGE) products.2 3 In fact, LDLs isolated from non–insulin-dependent diabetics (NIDDM) contain higher levels of AGE products and conjugated dienes and are more easily oxidized by copper than native LDL.4 In addition, plasma from patients whose insulin-dependent diabetes mellitus (IDDM) is poorly controlled has less antioxidant capacity.5
Recently, a series of bioactive prostaglandin (PG)
F2-like compounds (isoprostanes) has been
discovered,6 which are produced from
arachidonic acid through a nonenzymatic process of
lipid peroxidation, catalyzed by oxygen free radicals on cell membranes
and LDL particles (reviewed in Reference 77 ). Among these products,
of particular importance is 8-iso-PGF2, which
induces vasoconstriction8 and modulates the function of
human platelets.9 10 11
F2-isoprostanes can be reliably measured in both plasma and urine12 13 and have been shown to be increased in association with advanced age,13 hypercholesterolemia,14 and cigarette smoking.15 16
We have previously reported biochemical evidence of persistent
platelet activation, as reflected by enhanced
11-dehydro-TXB2 (TXM) excretion, in NIDDM
patients with macrovascular complications and shown that this
abnormality was partially reversible in association with improved
glycemic control.17 We speculated that increased oxidant
stress in diabetes could induce enhanced generation of
8-iso-PGF2 and other biologically active
iso-eicosanoids and that these compounds could in turn contribute to
platelet activation in this setting. Therefore, in the present
study, we investigated whether 8-iso-PGF2
formation is altered in NIDDM patients when compared with age-matched
nondiabetic subjects and whether it correlates with the rate of
TXA2 biosynthesis. We also measured
F2-isoprostane formation in IDDM patients as
compared with their age-matched control subjects to assess the relative
contribution to oxidant stress of the diabetic metabolic
abnormality per se, vis-à-vis the macrovascular complications
often accompanying NIDDM. Moreover, we examined the effects of 2
interventions potentially capable of reducing oxidant stress, that is,
improvement in metabolic control and vitamin E
supplementation, by assessing time-related changes in urinary
8-iso-PGF2 and TXM excretion in NIDDM.
The results of the present study suggest that enhanced peroxidation of arachidonic acid to form biologically active isoprostanes may represent an important biochemical link between impaired glycemic control and persistent platelet activation in this setting.
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Methods |
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Subjects
Eighty-five patients with diabetes mellitus were studied on several occasions between May 1995 and December 1997. Sixty-two had NIDDM and 23 had IDDM, as defined in accordance with the criteria of the American Diabetes Association.18 Sixty-two and 23 healthy subjects, age- and sex-matched with the NIDDM and IDDM patients, respectively, were also studied. The baseline characteristics of patients and control subjects are detailed in Table 1
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Of the 62 NIDDM patients, 20 patients had a history or physical examination positive for evidence of macrovascular complications. Twelve patients had stable angina pectoris or had had a myocardial infarction, and 8 had peripheral vascular disease. Patients with coronary heart disease were in a stable phase. Patients with peripheral vascular disease were in Fontaine stage II (intermittent claudication, ankle-arm pressure index of <0.85, and no resting pain), with a constant level of pain while walking. At the time of the study, NIDDM patients were being treated by diet alone (4 patients), insulin alone (6 patients), or by diet plus oral hypoglycemic agents (metformin and/or sulfonylureas) (43 patients); in 9 patients, insulin was added to the oral hypoglycemic agents. Twenty-four patients had arterial hypertension, defined as current systolic/diastolic blood pressure >140/90 mm Hg. Twenty-six patients were hypercholesterolemic (blood cholesterol level >240 mg/dL).
None of the 23 IDDM patients had a history or physical examination positive for evidence of macrovascular complications. Nine patients had diabetic retinopathy as determined by direct ophthalmoscopy through a dilated pupil. Only 1 IDDM patient was hypertensive as defined above. At the time of the study, all IDDM patients were being treated with insulin therapy.
Patients with renal insufficiency or proteinuria (by serum creatinine levels and urinalysis), altered hepatic function (by liver enzymes), or alcohol abuse (by clinical history and laboratory measurements) were excluded. Both diabetic patients and healthy subjects were selected for being nonsmokers at the time of study to eliminate a potential confounder.
Informed consent was obtained from each participating subject, and the protocol was approved by the ethical committee of the University of Chieti Medical School.
Design of the Studies
In the first study, a cross-sectional comparison of urinary
8-iso-PGF2 and TXM, a major enzymatic
metabolite of TXA2, was performed between
patients and control subjects. All the subjects were studied as
outpatients after a 12-hour fast. Each patient performed an overnight
urine collection, immediately before blood sampling. Urine samples were
added with the antioxidant 4-hydroxy-tempo (1 mmol/L) (Sigma
Chemical Co) and stored at -20°C until extraction.
Because small amounts of 8-iso-PGF2 can be
formed by human platelets and monocytes through a
cyclooxygenase-dependent mechanism,7 a
second study was performed to evaluate whether inhibition of
cyclooxygenase activity had any influence on
8-iso-PGF2 excretion in diabetes. For this
purpose, 6 of the 62 NIDDM patients (3 women and 3 men; 56 to 75 years
of age) were given 50 mg acetylsalicylic acid once
daily and 200 mg indobufen (a reversible
cyclooxygenase inhibitor) twice daily,
each drug for 7 days in 2 successive weeks, according to a randomized
sequence. These patients collected overnight urine samples before
dosing and on the last day of each treatment for measurement of
8-iso-PGF2 and TXM excretion.
To assess the potential influence of improved metabolic
control on F2-isoprostane formation and
platelet activation, a third study was performed in 21 NIDDM
patients (13 women and 8 men; 39 to 75 years of age). At the time of
the cross-sectional study, these 21 NIDDM patients were in poor
metabolic control (fasting blood glucose >200 mg/dL,
glycohemoglobin [HbA1c] >9%) despite taking
oral antidiabetic agents for months. These patients were examined twice
weekly over a 4-week period for blood glucose monitoring, and oral
antidiabetic therapy was adjusted accordingly and/or insulin therapy
was instituted to achieve improved metabolic control.
Throughout the study, patients followed an isocaloric diet that
provided 50% of calories as carbohydrates, 30% as fat, and 20% as
protein. The level of dietary cholesterol was 
0.3 g per
day. Physical activity was encouraged, and patients were instructed to
walk at least 30 minutes after each meal. No patient experienced a
hypoglycemic reaction during the study period. Blood and overnight
urine samples were obtained before and at the end of this intensive
monitoring and treatment program for determination of fasting glucose
and HbA1c levels and
8-iso-PGF2 and TXM excretion,
respectively.
To investigate the short-term effects of antioxidant intervention on
urinary 8-iso-PGF2 and TXM excretion, vitamin
E was given to 10 (6 women and 4 men; 42 to 69 years of age) of the 62
NIDDM patients. They were given 600 mg/d, l--tocopherol
acetate (Evion) daily for 2 weeks after a baseline evaluation. This
dose of vitamin E is 60-fold higher than the recommended daily
dietary allowance. Before and after vitamin E supplementation, they
collected an overnight urine sample for measurement of
8-iso-PGF2 and TXM and had a fasting blood
sample drawn for lipid levels, plasma and LDL vitamin E, and oxidation
of isolated LDL in vitro.
Urinary Eicosanoid Assays
Urinary 8-iso-PGF2 and TXM were
measured by previously described radioimmunoassay
methods.13 19 Measurements of urinary
8-iso-PGF2 and TXM by these radioimmunoassays
have been validated with the use of different antisera and by
comparison with gas chromatography/mass spectrometry,
as detailed elsewhere.13 19
Lipid Measurements
All blood samples for lipid studies were drawn into EDTA (1
mg/mL and separated within 1 hour after sampling. Total, LDL and
high-density lipoprotein cholesterol,
triglycerides, and vitamin E were determined as previously
described.14 Aliquots of the plasma in EDTA, immediately
after separation, were stored at -80°C until LDL isolation. LDL was
isolated by single vertical spin density gradient
ultracentrifugation, and LDL protein,
cholesterol, and vitamin E were determined as previously
described.14 To induce oxidation, LDL (0.2 mg
cholesterol/mL) was incubated with 5 mmol/L
CuSO4 in PBS, pH 7.4, at 37°C. The formation of
conjugated dienes was determined
spectrophotometrically.14
Clinical Laboratory Measurements
Fasting plasma glucose was measured by the glucose oxidase
method. HbA1C level was measured by automated
high-performance liquid chromatography.
Statistical Analysis
The data were analyzed by nonparametric
methods to avoid assumptions about the distribution of the measured
variables. 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±1 SD.
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Results |
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Urinary 8-iso-PGF2
excretion was
significantly (P=0.0001) higher in NIDDM patients (419±208
pg/mg creatinine; mean±SD, n=62) than in age-matched
healthy subjects (208±92 pg/mg creatinine) (Figure 1). Twenty-six of the 62 NIDDM had blood
cholesterol >240 mg/dL (292±37) and abnormal LDL
cholesterol levels (189±38 mg/dL). The urinary excretion
of 8-iso-PGF2 was not significantly higher in
these hypercholesterolemic patients than in the 36
normocholesterolemic NIDDM patients (438±178 vs
401±227 pg/mg creatinine). Similarly, no statistically
significant differences in urinary 8-iso-PGF2
were found between hypertensive and normotensive NIDDM patients
(429±219 vs 412±203 pg/mg creatinine) nor between those
with and those without macrovascular complications (459±233 vs
400±195 pg/mg creatinine).
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Consistent with previous findings, NIDDM patients had
significantly enhanced TXM excretion versus that in control subjects
(1103±1068 vs 415±244 pg/mg creatinine;
P=0.0001). A statistically significant correlation was found
between TXM and 8-iso-PGF2 excretion in NIDDM
patients (r=0.39, P=0.0023).
The urinary excretion of 8-iso-PGF2 was also
increased in the group of IDDM patients (400±146 pg/mg
creatinine; n=23) as compared with their age-matched
control subjects (197±69 pg/mg creatinine;
P=0.0001) (Figure 2).
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Effects of Cyclooxygenase Inhibition
Two structurally unrelated cyclooxygenase
inhibitors, aspirin and indobufen, were used to investigate
the mechanism(s) of F2-isoprostane formation in
NIDDM. As shown in Figure 3, urinary
8-iso-PGF2 excretion was largely unaffected
during 2 successive weeks of cyclooxygenase
inhibition achieved with either agent, despite normalization of TXM
excretion. This finding is consistent with a
noncyclooxygenase mechanism of
F2-isoprostane formation as characterized in
other clinical settings.13 14 20
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This study also allowed assessing the reproducibility of
8-iso-PGF2 excretion in NIDDM on the basis of
3 different urine collections performed over a 2-week period in 6
patients. The intrasubject coefficient of variation of these
measurements averaged 19±11%.
Influence of Metabolic Control
Twenty-one NIDDM patients who had not achieved adequate
metabolic control (fasting blood glucose >200 mg/dL and
HbA1c >9%) despite oral antidiabetic therapy
were subjected to intensive monitoring and treatment over 4 weeks, and
blood and urine samples were obtained before and after improved
metabolic control. At the end of this period,
HbA1c fell from 9.9±1.3% to 7.5±1.0%
(P<0.0001), and fasting blood glucose was significantly
reduced from 306±118 to 159±47 mg/dL (P<0.0001).
Improvement in metabolic control was associated with a
statistically significant reduction in both
8-iso-PGF2 (from 533±276 to 365±226 pg/mg
creatinine; P=0.0001) (Figure 4) and TXM (from 1643±1269 to 975±726
pg/mg creatinine; P=0.0005) excretion.
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Effects of Vitamin E Supplementation
We also examined the effects of vitamin E supplementation (600 mg
daily for 2 weeks) on the urinary excretion of
8-iso-PGF2 and TXM to test the hypothesis of a
cause-and-effect relation between enhanced lipid peroxidation and
platelet activation in NIDDM. Vitamin E supplementation was
associated with statistically significant changes in plasma vitamin E
levels, vitamin E content of LDL, and lag time for LDL oxidation (Table 2). As depicted in Figure 5, vitamin E supplementation was
associated with a statistically significant reduction in urinary
8-iso-PGF2 and TXM, by 37% and 43%,
respectively. A statistically significant correlation was found between
the 2 sets of measurements (r=0.582; P=0.0112).
Individual values of 8-iso-PGF2 fell within
the normal range in all NIDDM patients treated with vitamin E.
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Discussion |
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We have previously demonstrated enhanced TXA2 biosynthesis in NIDDM patients and provided evidence for its platelet origin and its reduction in response to tight metabolic control.17 Furthermore, a recently completed study21 suggests that the metabolic disorder rather than the attendant vascular disease is responsible for persistent platelet activation in NIDDM. In the present report, we performed a series of studies to test the hypothesis that persistent platelet activation may, at least in part, be related to enhanced formation of biologically active products of arachidonic acid peroxidation.
Previous evidence for enhanced lipid peroxidation in diabetes mellitus
is largely indirect and based on crude measurements of lipid oxidation
products in plasma22 23 24 or the susceptibility of the
patient's LDL to oxidation in vitro.25 26 27 Our study has
used the urinary excretion of the F2-isoprostane
8-iso-PGF2 as a marker of in vivo lipid
peroxidation.7
We found that the formation and urinary excretion of
8-iso-PGF2 was abnormally elevated in the vast
majority of a relatively large group of NIDDM patients carefully
characterized for other variables potentially influencing lipid
peroxidation. Thus we excluded the contribution of advanced age by
adequate age-matching of individual patients and control subjects and
of cigarette smoking by only recruiting nonsmokers into the study.
Similarly, differences in 8-iso-PGF2 formation
between diabetic patients and healthy subjects could not be accounted
for by the presence of macrovascular complications,
arterial hypertension, or
hypercholesterolemia.
We found a highly significant correlation between blood glucose and
urinary 8-iso-PGF2, suggesting that lipid
peroxidation may be, at least in part, related to the determinants of
glycemic control. This observation is consistent with the in
vitro findings of Natarajan et al,28 who demonstrated
enhanced formation and release of 8-iso-PGF2
by porcine vascular smooth muscle cells cultured under hyperglycemic
conditions. Gopaul et al29 previously reported increased
plasma levels of esterified 8-iso-PGF2 in
NIDDM that did not correlate with fasting glucose or with
HbA1c. Whether the greater variability in plasma
versus urinary measurements of this
F2-isoprostane or the small sample size of the
latter study contribute to this apparent discrepancy remains unanswered
by the present study.
That impaired glycemic control rather than the attendant macrovascular
complications is responsible for enhanced formation of
F2-isoprostanes in NIDDM is also supported by the
similar findings in IDDM patients (Figure 2
). Catella-Lawson et
al30 have recently reported a trend toward increased
urinary 8-iso-PGF2 excretion in a group of 18
diabetics, with statistically significant elevations in patients with
diabetic ketoacidosis.
We further examined the relation between metabolic control
and F2-isoprostane formation by studying 21 NIDDM
patients with inadequate glycemic control, before and after intensive
antidiabetic treatment, and closer monitoring. Reduced blood glucose
levels were associated with a fall in urinary
8-iso-PGF2 excretion rates, the average extent
of which showed a remarkably good fitting, with the linear relation
between blood glucose and urinary 8-iso-PGF2,
as established in the whole group of NIDDM patients under baseline
conditions. Improvement of metabolic control in these
patients was accompanied by a statistically significant reduction in
TXM excretion by 41% as compared with 45% in the previous study
carried out with a similar protocol.17 On the basis of
these findings, it is tempting to speculate that changes in the rate of
arachidonate peroxidation to form biologically active
iso-eicosanoids, such as 8-iso-PGF2, may
represent an important biochemical link between altered
glycemic control, oxidant stress, and platelet activation in
NIDDM.
That changes in F2-isoprostane formation
are not merely a consequence of persistent platelet activation is
clearly indicated by the study with 2 structurally unrelated
cyclooxygenase inhibitors. Thus 70%
reduction in TXM excretion-corresponding to complete normalization of
TXA2 biosynthesis-was not accompanied by any
detectable change in urinary 8-iso-PGF2
excretion. This finding is consistent with the
noncyclooxygenase mechanism of formation of
8-iso-PGF2 in other clinical settings
characterized by enhanced lipid peroxidation.7 14
Having established that formation of
8-iso-PGF2 is largely independent of
cyclooxygenase activity, we set out to assess the
reversibility of its increase in response to vitamin E supplementation.
We choose a pharmacological dose of vitamin E, 600 mg daily, based on
the results of a similar study performed in
hypercholesterolemic patients14
demonstrating dose-dependent reduction in
F2-isoprostane formation in response to
short-term vitamin E supplementation. Similar to the results obtained
in hypercholesterolemic patients, we found virtually
complete normalization of 8-iso-PGF2 excretion
in NIDDM in the present study. Moreover, changes in
F2-isoprostane formation were accompanied by
similar reductions in TXM excretion, consistent with a
cause-and-effect relation between enhanced lipid peroxidation and
persistent platelet activation in this setting.
Concentrations of 8-iso-PGF2 in the range of 1
nmol/L to 1 µmol/L induce a dose-dependent increase in
platelet shape change, calcium release from intracellular stores,
and inositol phosphates.9 10 11 Moreover,
8-iso-PGF2 increases platelet adhesion and
reduces the antiadhesive and antiaggregatory effects of nitric
oxide.31 Furthermore, 8-iso-PGF2
causes dose-dependent, irreversible platelet aggregation in the
presence of concentrations of collagen, ADP,
arachidonic acid, and
PGH2/TXA2 analogues that
when acting alone fail to aggregate platelets.11
Although platelet-active concentrations of
8-iso-PGF2 may not be achieved in circulating
blood, it should be pointed out that this compound is but one of a
series of biologically active iso-eicosanoids formed through a similar
noncyclooxygenase mechanism of lipid
peroxidation.32
We believe that our results have potential clinical implications for
the prevention of atherothrombosis in diabetic patients. Given the
relatively limited impact of conventional antiplatelet prophylaxis
in this setting,33 the present findings suggest the
opportunity of exploring combined preventive strategies based on the
combination of low-dose aspirin and vitamin E supplementation. The
urinary excretion of 8-iso-PGF2 provides a
noninvasive, reproducible biochemical end point for dose-finding
studies of vitamin E supplementation.7 This may help
resolve the present uncertainty about the optimal dose of vitamin E
and provide a more rational basis for dose selection for large-scale
intervention trials.
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Acknowledgments |
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This study was supported by grants from Progetto Strategico "Infarto," Consiglio Nazionale delle Ricerche (CNR) (96.052685.T74 and 97.04882.ST74), and Progetto Finalizzato Prevenzione e Controllo dei Fattori di Malattia, CNR (SP8: 95.00882.PF41 and 95.00807.PF41). We wish to thank Domenico De Cesare, Salvatore Roccaforte, Antonio Colangelo, Andrea Salvati, Antonina Legnino, Lia Cucco, and Lorella Cesarone for assistance with the clinical studies.
Received June 18, 1998; revision received September 18, 1998; accepted October 1, 1998.
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R. De Caterina, F. Cipollone, F. P. Filardo, M. Zimarino, W. Bernini, G. Lazzerini, T. Bucciarelli, A. Falco, P. Marchesani, R. Muraro, et al. Low-Density Lipoprotein Level Reduction by the 3-Hydroxy-3-Methylglutaryl Coenzyme-A Inhibitor Simvastatin Is Accompanied by a Related Reduction of F2-Isoprostane Formation in Hypercholesterolemic Subjects: No Further Effect of Vitamin E Circulation, November 12, 2002; 106(20): 2543 - 2549. [Abstract] [Full Text] [PDF]
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L. Fontana, C. Giagulli, L. Cominacini, A. F. Pasini, P. Minuz, A. Lechi, A. Sala, and C. Laudanna {beta}2 Integrin-Dependent Neutrophil Adhesion Induced by Minimally Modified Low-Density Lipoproteins Is Mainly Mediated by F2-Isoprostanes Circulation, November 5, 2002; 106(19): 2434 - 2441. [Abstract] [Full Text] [PDF]
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R. J Woodman, T. A Mori, V. Burke, I. B Puddey, G. F Watts, and L. J Beilin Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension Am. J. Clinical Nutrition, November 1, 2002; 76(5): 1007 - 1015. [Abstract] [Full Text] [PDF]
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G. Davi, M. T. Guagnano, G. Ciabattoni, S. Basili, A. Falco, M. Marinopiccoli, M. Nutini, S. Sensi, and C. Patrono Platelet Activation in Obese Women: Role of Inflammation and Oxidant Stress JAMA, October 23, 2002; 288(16): 2008 - 2014. [Abstract] [Full Text] [PDF]
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U. Riserus, S. Basu, S. Jovinge, G. N. Fredrikson, J. Arnlov, and B. Vessby Supplementation With Conjugated Linoleic Acid Causes Isomer-Dependent Oxidative Stress and Elevated C-Reactive Protein: A Potential Link to Fatty Acid-Induced Insulin Resistance Circulation, October 8, 2002; 106(15): 1925 - 1929. [Abstract] [Full Text] [PDF]
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H.-Y. Huang, L. J Appel, K. D Croft, E. R Miller III, T. A Mori, and I. B Puddey Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial Am. J. Clinical Nutrition, September 1, 2002; 76(3): 549 - 555. [Abstract] [Full Text] [PDF]
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R. D. Hoeldtke, K. D. Bryner, D. R. McNeill, G. R. Hobbs, J. E. Riggs, S. S. Warehime, I. Christie, G. Ganser, and K. Van Dyke Nitrosative Stress, Uric Acid, and Peripheral Nerve Function in Early Type 1 Diabetes Diabetes, September 1, 2002; 51(9): 2817 - 2825. [Abstract] [Full Text] [PDF]
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M. A. Forgione, A. Cap, R. Liao, N. I. Moldovan, R. T. Eberhardt, C. C. Lim, J. Jones, P. J. Goldschmidt-Clermont, and J. Loscalzo Heterozygous Cellular Glutathione Peroxidase Deficiency in the Mouse: Abnormalities in Vascular and Cardiac Function and Structure Circulation, August 27, 2002; 106(9): 1154 - 1158. [Abstract] [Full Text] [PDF]
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 J. D. Krier, M. Rodriguez-Porcel, P. J. M. Best, J. C. Romero, A. Lerman, and L. O. Lerman Vascular responses in vivo to 8-epi PGF2alpha in normal and hypercholesterolemic pigs Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R303 - R308. [Abstract] [Full Text] [PDF]
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E. D. Aymong, M. J. Curtis, M. Youssef, M. M. Graham, L. Shewchuk, W. Leschuk, and T. J. Anderson Abciximab Attenuates Coronary Microvascular Endothelial Dysfunction After Coronary Stenting Circulation, June 25, 2002; 105(25): 2981 - 2985. [Abstract] [Full Text] [PDF]
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K. Foo and A. D Timmis Review: Managing the diabetic patient with angina The British Journal of Diabetes & Vascular Disease, May 1, 2002; 2(3): 169 - 175. [Abstract] [PDF]
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T. Ide, H. Tsutsui, N. Ohashi, S. Hayashidani, N. Suematsu, M. Tsuchihashi, H. Tamai, and A. Takeshita Greater Oxidative Stress in Healthy Young Men Compared With Premenopausal Women Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 438 - 442. [Abstract] [Full Text] [PDF]
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S. Devaraj, A. V. C. Chan Jr., and I. Jialal {alpha}-Tocopherol Supplementation Decreases Plasminogen Activator Inhibitor-1 and P-Selectin Levels in Type 2 Diabetic Patients Diabetes Care, March 1, 2002; 25(3): 524 - 529. [Abstract] [Full Text] [PDF]
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M. J. Sampson, N. Gopaul, I. R. Davies, D. A. Hughes, and M. J. Carrier Plasma F2 Isoprostanes: Direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes Diabetes Care, March 1, 2002; 25(3): 537 - 541. [Abstract] [Full Text] [PDF]
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A. Nitenberg, S. Ledoux, P. Valensi, R. Sachs, and I. Antony Coronary Microvascular Adaptation to Myocardial Metabolic Demand Can Be Restored by Inhibition of Iron-Catalyzed Formation of Oxygen Free Radicals in Type 2 Diabetic Patients Diabetes, March 1, 2002; 51(3): 813 - 818. [Abstract] [Full Text] [PDF]
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 Y Fukuda, H Teragawa, K Matsuda, T Yamagata, H Matsuura, and K Chayama Tetrahydrobiopterin restores endothelial function of coronary arteries in patients with hypercholesterolaemia Heart, March 1, 2002; 87(3): 264 - 269. [Abstract] [Full Text] [PDF]
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F. Violi, L. Iuliano, and G. A. FitzGerald Reply J. Am. Coll. Cardiol., February 6, 2002; 39(3): 554 - 555. [Full Text] [PDF]
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 S. A. Dillon, G. M. Lowe, D. Billington, and K. Rahman Dietary Supplementation with Aged Garlic Extract Reduces Plasma and Urine Concentrations of 8-Iso-Prostaglandin F2{alpha} in Smoking and Nonsmoking Men and Women J. Nutr., February 1, 2002; 132(2): 168 - 171. [Abstract] [Full Text] [PDF]
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M. S. Sabatine and E. Braunwald Will Diabetes Save the Platelet Blockers? Circulation, December 4, 2001; 104(23): 2759 - 2761. [Full Text] [PDF]
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A Liguori, P Abete, J.M Hayden, F Cacciatore, F Rengo, G Ambrosio, D Bonaduce, M Condorelli, P.D Reaven, and C Napoli Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1 Eur. Heart J., November 2, 2001; 22(22): 2075 - 2084. [Abstract] [PDF]
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J. I. Osende, J. J. Badimon, V. Fuster, P. Herson, P. Rabito, R. Vidhun, A. Zaman, O. J. Rodriguez, E. I. Lev, U. Rauch, et al. Blood thrombogenicity in type 2 diabetes mellitus patients is associated with glycemic control J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1307 - 1312. [Abstract] [Full Text] [PDF]
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S. Devaraj, S. V. Hirany, R. F. Burk, and I. Jialal Divergence between LDL Oxidative Susceptibility and Urinary F2-Isoprostanes as Measures of Oxidative Stress in Type 2 Diabetes Clin. Chem., November 1, 2001; 47(11): 1974 - 1979. [Abstract] [Full Text] [PDF]
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S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
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J.-L. CRACOWSKI, C. CRACOWSKI, G. BESSARD, J.-L. PEPIN, J. BESSARD, C. SCHWEBEL, F. STANKE-LABESQUE, and C. PISON Increased Lipid Peroxidation in Patients with Pulmonary Hypertension Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 1038 - 1042. [Abstract] [Full Text] [PDF]
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G. Davi, G. Di Minno, A. Coppola, G. Andria, A. M. Cerbone, P. Madonna, A. Tufano, A. Falco, P. Marchesani, G. Ciabattoni, et al. Oxidative Stress and Platelet Activation in Homozygous Homocystinuria Circulation, September 4, 2001; 104(10): 1124 - 1128. [Abstract] [Full Text] [PDF]
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J. W. Heinecke Is the Emperor Wearing Clothes?: Clinical Trials of Vitamin E and the LDL Oxidation Hypothesis Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1261 - 1264. [Abstract] [Full Text] [PDF]
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J. D O'Reilly, A. I Mallet, G. T McAnlis, I. S Young, B. Halliwell, T. A. Sanders, and H. Wiseman Consumption of flavonoids in onions and black tea: lack of effect on F2-isoprostanes and autoantibodies to oxidized LDL in healthy humans Am. J. Clinical Nutrition, June 1, 2001; 73(6): 1040 - 1044. [Abstract] [Full Text] [PDF]
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