© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Enhanced In Vivo Lipid Peroxidation at Elevated Plasma Total Homocysteine Levels
From the Research Institute of Public Health, University of Kuopio, Kuopio, Finland (S.V., K.N., J.T.S.), the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (J.D.M., L.J.R.), the Departments of Nutrition (G.A.), and Mental Health and Alcohol Research (H.A.), National Public Health Institute, Helsinki, Finland.
Correspondence to Dr J.T. Salonen, Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. E-mail Salonen{at}reivi.uku.fi
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Abstract |
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Abstract—An elevated plasma total homocysteine level (tHcy) is considered an independent risk factor for atherosclerosis. The mechanisms by which hyperhomocysteinemia induces atherosclerosis are only partially understood, but promotion of LDL oxidation and endothelial injury have been suggested. The purpose of this study was to test the hypothesis that a high plasma tHcy is associated in men with increased in vivo lipid peroxidation, as measured by plasma F2-isoprostane concentrations. We investigated this association in a subset of the participants in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Of 256 male participants, a subsample of 100 consecutive men was selected for F2-isoprostane assays. The mean tHcy was 11.0 µmol/L, and the mean F2-isoprostanes was 29.6 ng/L. The simple correlation coefficient for association between tHcy and F2-isoprostane was 0.40 (P<0.001). In a linear regression model, the variables with the strongest associations with F2-isoprostane were tHcy (standardized coefficient 0.33, P<0.001), serum triglycerides (0.21, P=0.042), carbohydrate-deficient transferrin (0.15, P=0.132), and plasma lipid-standardized
-tocopherol (-0.11,
P=0.252) (R2=0.24,
P<0.001 for model). Plasma F2-isoprostane
levels increased linearly across quintiles of tHcy
(P<0.001). The unadjusted mean (95% confidence
interval) F2-isoprostanes was 47.5% greater in the highest
tHcy quintile (37.4, 31.1 to 43.6 ng/L) than in the lowest quintile
(25.3, 21.3 to 29.3 ng/L). Adjustment for the strongest other
determinants of F2-isoprostane reduced this difference to
28.2% (P=0.010). Our present data suggest that
elevated fasting plasma tHcy is associated with enhanced in vivo lipid
peroxidation in men.
Key Words: homocysteine • F2-isoprostanes • lipid peroxidation • cardiovascular diseases
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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An elevated plasma total homocysteine level (referred to as tHcy), the sum of all homocysteine species in plasma, including free and protein-bound forms, has been suggested as an independent risk factor for atherosclerosis.1 Several studies have demonstrated elevated plasma tHcy levels in patients with coronary, cerebrovascular, or peripheral vascular diseases, compared with controls. This association is strong and independent of other risk factors for atherosclerosis, and it is not only limited to severe hyperhomocysteinemia but observed also when tHcy is only moderately elevated.1 The mechanisms by which hyperhomocysteinemia may induce atherogenesis are only partially understood,2 but promotion of LDL oxidation and endothelial injury have been suggested.
There is evidence from epidemiologic studies that implicates a role for lipid peroxidation in atherogenesis.3 4 Standardized methods for the assessment of lipid peroxidation in vivo have been lacking. F2-isoprostanes are a recently described class of prostaglandin-like compounds that are produced by free radical–mediated lipid peroxidation of arachidonic acid independent of cyclooxygenase.5 The quantification of F2-isoprostanes in plasma has proven to be a valuable method in assessing lipid peroxidation in vivo.6 7 Although epidemiological evidence about the association between plasma F2-isoprostanes and cardiovascular diseases is limited, increased amounts of F2-isoprostanes have been found in human atherosclerotic lesions when compared with nonatherosclerotic vessel walls.8 9 Alfthan et al10 reported an association between mean plasma tHcy concentration and mortality from cardiovascular disease (CVD) in WHO Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) data. Their data show that cross-country differences in plasma tHcy concentrations are real and not caused by noncomparable sampling and assay procedures. The correlation coefficient for plasma tHcy and CVD mortality was 0.71. The highest CVD mortality and mean plasma tHcy concentration both were observed in Finland.
The purpose of this study was to test the hypothesis that plasma tHcy concentration is associated in men with enhanced lipid peroxidation in vivo, as measured by plasma F2-isoprostane concentrations.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We studied this association in a subset of the participants in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study.11 The ASAP study is a balanced 2x2 factorial double-masked placebo-controlled randomized clinical trial to study the effects of vitamin C and E supplementation on oxidative stress, lipid peroxidation, atherosclerotic progression, blood pressure, and cataract formation in humans. The study protocol was approved by the Research Ethics Committee of the University of Kuopio. From 256 male participants, a subsample of 100 consecutive men were selected for F2-isoprostane assays.
For the present study, all measurements were done at the baseline visit between April and October 1995. The age of these men was 58.6±6.5 years (mean±SD), and their serum total cholesterol was 6.14±0.93 mmol/L.
Subjects were instructed to abstain from eating for 12 hours and from ingesting alcohol for a week. After a subject had rested in sitting position for 5 minutes, blood was drawn into Venoject vacuum tubes (Terumo Corp). On the day before blood drawing, a 24-hour urine was collected.
Plasma F2-isoprostane concentrations were
determined at Vanderbilt University Medical Center, Nashville, Tenn, in
1997. A deuterated prostaglandin
F2 internal standard was added to plasma, and
F2-isoprostanes were extracted with
C18 and silica minicolumns. Compounds were
converted to pentafluorobenzyl ester trimethylsilyl ether derivatives
and analyzed by a gas chromatographic–mass
spectrometric assay.12 The coefficient of variation for
both intraday and interday variation was 9%.
Plasma tHcy concentrations were measured at the National Public Health Institute, Helsinki, Finland, essentially as described by Araki and Sako.13 Homocystine, other mixed disulfides, and the protein-bound homocysteine were first reduced to free homocysteine by tributylphosphine, and tHcy was measured using an isocratic reversed-phase HPLC method with fluorescence detection as described earlier in detail.10 The coefficient of variation between series was 7%.
Plasma -tocopherol and ß-carotene were determined by
HPLC, and serum lipids were quantified photometrically at the Research
Institute of Public Health, Kuopio, Finland, as described
earlier.11 Urinary nicotine metabolite 24-hour excretion
was measured by a colorimetric method (Erilab). To
separate the effect of -tocopherol from that of serum
lipids, values of lipid-standardized -tocopherol were
used in the statistical analysis.14
The measurement of serum carbohydrate-deficient transferrin (CDT) is based on alcohol-altered glycosylation process of transferrin. Resulting transferrin is missing carbohydrate terminal chains, including sialic acid, galactose, and N-acetylglucosamine, thus the term carbohydrate-deficient transferrin. This modified transferrin was separated by anion-exchange chromatography followed by RIA (DCTect, Pharmacia & Upjohn Diagnostics). The analyses were performed in duplicate.
The statistical significance of a linear trend in plasma
F2-isoprostane over quintiles of tHcy was tested
using SPSS 1-way ANOVA, with 95% confidence intervals (CI) estimated
taking into account the number of tHcy categories. A stepwise linear
multivariate regression analysis was used to
find the strongest other determinants of plasma
F2-isoprostanes
(Table
). Those were used as covariates in
an analysis of covariance to estimate the independent
association of tHcy with F2-isoprostanes.
Differences in covariates between tHcy categories were adjusted with
linear covariance correction.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The mean plasma tHcy was 11.0 µmol/L, and the mean of F2-isoprostanes 29.6 ng/L. The simple correlation coefficient for association between plasma tHcy and F2-isoprostane was 0.40 (P<0.001). This correlation was 0.40 (P=0.003) in 50 men whose serum total cholesterol was below the median (6.07 mmol/L) and 0.42 (P=0.003) in 50 men with a higher serum cholesterol. In a linear regression model, the variables with the strongest associations with F2-isoprostanes were tHcy (standardized coefficient 0.33, P<0.001), serum triglycerides (0.21, P=0.042), CDT (0.15, P=0.132), and plasma lipid-standardized
-tocopherol (-0.11,
P=0.252) (R2=0.24,
P<0.001 for model) (Table
).
Plasma F2-isoprostane levels increased linearly
across the quintiles of plasma tHcy (P<0.001 for linear
trend, Figure). The unadjusted mean (95%
CI) of F2-isoprostanes was 47.5% greater in the
highest tHcy quintile (37.4, 31.1 to 43.6 ng/L) than in the lowest
quintile (25.3, 21.3 to 29.3 ng/L). Adjustment for the strongest other
determinants of F2-isoprostane reduced this
difference to 28.2% (P=0.010). In the multiple range test,
the F2-isoprostane mean was significantly
(P<0.05) higher in the 2 highest tHcy quintiles compared
with the lowest quintile. History of smoking or the proportion of men
with diabetes mellitus did not differ significantly between plasma tHcy
quintiles.
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We also compared the group with an elevated tHcy (>12 µmol/L)
with the low tHcy group (
12 µmol/L) with and without
adjustment for the strongest other determinants of
F2-isoprostane. The unadjusted mean (95% CI)
F2-isoprostanes were 34% greater in the high
tHcy group (36.0, 31.0 to 41.0 ng/L) compared with the low tHcy group
(26.8, 24.3 to 29.2 ng/L; P<0.001). Adjustment for other
strongest determinants shown in the Table reduced this difference to
22.1% (P=0.018).
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Discussion |
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To our knowledge, this is the first study to show that a high fasting plasma tHcy is associated with enhanced lipid peroxidation in vivo in men. Lipid peroxidation was assessed in this study by quantifying plasma F2-isoprostanes. These are prostaglandin-like products of nonenzymatic lipid peroxidation.5 Measurement of endogenous unmetabolized F2-isoprostanes has proven to be a valuable approach to assess lipid peroxidation in vivo.6 7 The method we used to quantify F2-isoprostanes measures the peak that coelutes with 8-iso-prostaglandin F2
but may contain other isoprostanes
as it is impossible to cleanly separate various isoprostane compounds
using this assay.12 Morrow and Roberts15 have
shown that quantification of this peak correlates with total
isoprostane production in all situations they have examined and
is thus an accurate index of lipid peroxidation. Although both retrospective and prospective epidemiological studies have shown that even moderate hyperhomocysteinemia is associated with an increased risk for premature vascular disease in the coronary, cerebral, and peripheral arteries,16 17 18 19 20 21 22 the risk-increasing mechanisms of the effect of plasma tHcy are still poorly understood. Homocysteine is readily oxidized when added to plasma, principally as a consequence of auto-oxidation leading to the formation of homocystine, homocysteine-mixed disulfides, and homocysteine thiolactone. It has been proposed that during the transition metal ion-catalyzed oxidation of the sulfhydryl group of homocysteine, hydrogen peroxide is formed, which promotes oxidative stress and lipid peroxidation through Fenton-type reactions.23 Formed hydrogen peroxide may also have direct harmful effects on the vascular endothelium.24 Homocysteine has also been shown to oxidize LDLs by reactions requiring redox-active transition metal ions.25 There is some evidence from animal models that supports the role of tHcy in lipid peroxidation. Young et al26 induced hyperhomocysteinemia in 8 pigs by intermittent exposure to nitrous oxide for 4 weeks and compared these with air-breathing control animals. At necropsy they measured cardiac tissue malondialdehyde and unsaturated fatty acid concentrations and concluded that hyperhomocysteinemia was associated with increased in vivo lipid peroxidation. In these hyperhomocysteinemic animals, plasma tHcy levels were much higher than in moderately hyperhomocysteinemic men. Durand et al27 studied acute methionine load-induced hyperhomocysteinemia and lipid peroxidation using a rat model. They found that a moderate hyperhomocysteinemia plays a role in the development of a thrombogenic state that might be mediated by the occurrence of lipid peroxidation, measured by an elevation of plasma conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances (TBARS).
Recently Domagala et al28 published a study about hyperhomocysteinemia in which lipid peroxidation was measured using the oral methionine-loading test. Study subjects were 46 men and women with normal or pathological methionine-loading test result. They reported a significant relationship between plasma homocysteine levels and lipid peroxidation, expressed as in an increase in TBARS. Our results at fasting state support these findings. Because some TBARS may be formed during the assay itself,29 measurement of endogenous unmetabolized F2-isoprostanes is probably a more reliable measurement of in vivo lipid peroxidation.
In conclusion, the present study provides the first evidence of a role for elevated fasting plasma tHcy in lipid peroxidation in vivo in men and suggests a plausible mechanism through which an elevated plasma tHcy could increase the risk of atherothrombotic CVD.
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Acknowledgments |
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This study was supported by NIH grants DK48831, GM42056, and GM15431 and grants from the Academy of Finland, the Yrjö Jahnsson Foundation and the Orion Research Foundation. We thank Kimmo Ronkainen for data analyses.
Received March 18, 1998; accepted September 1, 1998.
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 P R J Ames, A Margarita, J D. Alves, C Tommasino, L Iannaccone, and V Brancaccio Anticardiolipin antibody titre and plasma homocysteine level independently predict intima media thickness of carotid arteries in subjects with idiopathic antiphospholipid antibodies Lupus, April 1, 2002; 11(4): 208 - 214. [Abstract] [PDF]
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Z. Bagi, Z. Ungvari, and A. Koller Xanthine Oxidase-Derived Reactive Oxygen Species Convert Flow-Induced Arteriolar Dilation to Constriction in Hyperhomocysteinemia: Possible Role of Peroxynitrite Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 28 - 33. [Abstract] [Full Text] [PDF]
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Y. Jang, J. H. Lee, O. Y. Kim, H. Y. Park, and S. Y. Lee Consumption of Whole Grain and Legume Powder Reduces Insulin Demand, Lipid Peroxidation, and Plasma Homocysteine Concentrations in Patients With Coronary Artery Disease: Randomized Controlled Clinical Trial Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2065 - 2071. [Abstract] [Full Text] [PDF]
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E. Svenungsson, K. Jensen-Urstad, M. Heimburger, A. Silveira, A. Hamsten, U. de Faire, J. L. Witztum, and J. Frostegard Risk Factors for Cardiovascular Disease in Systemic Lupus Erythematosus Circulation, October 16, 2001; 104(16): 1887 - 1893. [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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S. N. Doshi, I. F. W. McDowell, S. J. Moat, D. Lang, R. G. Newcombe, M. B. Kredan, M. J. Lewis, and J. Goodfellow Folate Improves Endothelial Function in Coronary Artery Disease : An Effect Mediated by Reduction of Intracellular Superoxide? Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1196 - 1202. [Abstract] [Full Text] [PDF]
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 J.C. Chambers and J.S. Kooner Homocysteine -- an innocent bystander in vascular disease? Eur. Heart J., May 1, 2001; 22(9): 717 - 719. [PDF]
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P.a. Aukrust, R. K. Berge, T. Ueland, E. Aaser, J. K. Damas, L. Wikeby, A. Brunsvig, F. Muller, K. Forfang, S. S. Froland, et al. Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes J. Am. Coll. Cardiol., February 1, 2001; 37(2): 485 - 491. [Abstract] [Full Text] [PDF]
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L. Fontana, C. Giagulli, P. Minuz, A. Lechi, and C. Laudanna 8-Iso-PGF2{{alpha}} Induces {beta}2-Integrin-Mediated Rapid Adhesion of Human Polymorphonuclear Neutrophils : A Link Between Oxidative Stress and Ischemia/Reperfusion Injury Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 55 - 60. [Abstract] [Full Text] [PDF]
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F. H. A. F. de Man, I. J. A. M. Jonkers, E. Schwedhelm, A. H. M. Smelt, W. Onkenhout, W. van Duyvenvoorde, R. Buytenhek, J. A. G. Leuven, R. Troost, A. van der Laarse, et al. Normal Oxidative Stress and Enhanced Lipoprotein Resistance to In Vitro Oxidation in Hypertriglyceridemia : Effects of Bezafibrate Therapy Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2434 - 2440. [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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D. W. Jacobsen Hyperhomocysteinemia and Oxidative Stress : Time for a Reality Check? Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1182 - 1184. [Full Text] [PDF]
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M. A. Mansoor, C. Bergmark, S. J. Haswell, I. F. Savage, P. H. Evans, R. K. Berge, A. M. Svardal, and O. Kristensen Correlation between Plasma Total Homocysteine and Copper in Patients with Peripheral Vascular Disease Clin. Chem., March 1, 2000; 46(3): 385 - 391. [Abstract] [Full Text] [PDF]
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