doi: 10.1161/01.CIR.0000014762.06201.06
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(Circulation. 2002;105:2107.)
© 2002 American Heart Association, Inc.
Current Perspective |
Is the Oxidative Modification Hypothesis Relevant to Human Atherosclerosis?
Do the Antioxidant Trials Conducted to Date Refute the Hypothesis?
From the Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, Calif.
Correspondence to Dr Daniel Steinberg, School of Medicine (0682), University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0682. E-mail dsteinberg{at}ucsd.edu
Key Words: atherosclerosis • coronary disease • antioxidants • trials • lipoproteins
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Introduction |
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Top
Introduction
Origins of the Oxidative...Several large-scale, double-blind, placebo-controlled trials have shown convincingly that neither ß-carotene1–3 nor vitamin E, alone3–5 or in combination with other antioxidant vitamins,6 reduces the risk of fatal or nonfatal infarction (or other hard clinical end points) in an unselected population of people with established coronary heart disease (CHD) or at high risk of CHD. Two end point trials, much smaller trials that used vitamin E, have reported positive results,7,8 and one trial, which used ultrasound, showed that a combination of vitamins E and C slowed the progression of carotid artery lesions.9However, these are far outweighed by the negative results in the other, much larger trials. Certainly there is no basis for recommending vitamin E supplementation to patients with CHD, especially because it may blunt the effectiveness of hypolipidemic therapy with statins and niacin.6 A surprisingly large fraction of cardiologists (
40%) have been recommending such regimens10 despite warnings that this use was premature.11 At first glance, it might seem that these negative results close the book and that additional clinical trials of any antioxidants would be pointless. Closer examination, we believe, will show that such a conclusion would be premature and inappropriate.12 The hypothesis that oxidative modification of LDL plays a significant role in atherogenesis in humans is not necessarily disproved by the failure of these particular clinical trials any more than a negative trial of an ineffectual antibiotic in Pneumococcal pneumonia would prove that pneumonia is not a bacterial disease. The oxidative modification hypothesis is not that vitamin E will ameliorate the human disease but that oxidative modification of LDL and/or other oxidative events play a significant role in human atherogenesis as it does in animal models of atherogenesis. A corollary of the hypothesis is that some appropriate antioxidant intervention, at some appropriate dosage, in appropriately selected patients over an appropriate time interval has the potential to improve prognosis. Otherwise, of course, the role of oxidation would remain of academic interest only. In the present report, we put the currently available information into context by briefly reviewing the origins of the LDL modification hypothesis and explaining why the trials to date have not adequately tested the basic hypothesis, as pointed out by a number of authors.12–21 It would be a mistake to jettison as irrelevant to humans a hypothesis that is so strongly supported by many epidemiological studies and by so many positive results in several animal models, including nonhuman primates, and with the use of several different antioxidant compounds.12 Instead, perhaps we should be reexamining the science underlying the hypothesis and asking what additional basic information we need to design trials that will appropriately test the hypothesis.
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Origins of the Oxidative Modification Hypothesis |
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The concept that circulating LDL must undergo some kind of structural modification before it becomes fully proatherogenic was put forward originally by the Brown and Goldstein laboratory.22 They discovered that the macrophage, the precursor of the cholesterol-loaded foam cell, took up native LDL at a rate insufficient to load the cell with cholesterol. They also pointed out that patients totally lacking the native LDL receptor nevertheless accumulate large amounts of cholesterol in their macrophages. Therefore, they postulated that modifications of LDL must occur, leading to uptake of the modified forms through receptors other than the classic LDL receptor, which they termed "scavenger receptors." Goldstein et al23 identified the first of these scavenger receptors, the acetyl LDL receptor, which was later cloned in Krieger’s laboratory and renamed scavenger receptor A.24 Subsequently, several other scavenger receptors have been identified.25,26 The fundamental correctness of this concept of LDL modification is now supported by many lines of evidence. Any scheme for the pathogenesis of atherosclerosis must include one or more modified forms of LDL and macrophage receptor(s) for them.
Oxidative stress may contribute to atherogenesis by mechanisms that are not necessarily linked to LDL oxidation. For example, free radical oxygen species such as superoxide anion can rapidly react with and inactivate nitric oxide, enhancing proatherogenic mechanisms (eg, leukocyte adherence to endothelium, impaired vasorelaxation, platelet aggregation).13 As pointed out by Landmesser and Harrison,13 vitamin E would be an inappropriate antioxidant in such a system because it reacts very slowly with superoxide. Oxidized LDL (OxLDL) itself can inactivate nitric oxide and induce the same proatherogenic processes, but OxLDL may not be an obligatory intermediate.
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Modifications of LDL That Might Be Involved |
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Several different modifications of LDL have been described that convert it to a form recognized by one or more macrophage scavenger receptors. Modifications that can favor foam cell formation in vitro include oxidation, aggregation, enzymatic modification, complexing with immunoglobulins, and possibly others.27 The best studied of these and the only one for which there is good in vivo data are oxidative modification. As reviewed elsewhere,12 six different antioxidant compounds (probucol, probucol analogues, vitamin E, coenzyme Q, diphenylphenylenediamine, and butylated hydroxytoluene) have been studied in four different animal models of atherosclerosis (rabbits, mice, hamsters, and monkeys) and most of the results have been strikingly positive. A number of important ancillary lines of evidence are consonant with the hypothesis, including the fact that oxidation of LDL has been shown to occur in vivo and that OxLDL is demonstrable in lesions; that autoantibodies are generated against OxLDL and that the titers are correlated with the extent of atherosclerosis; that knocking out scavenger receptors (either scavenger receptor A or CD36) ameliorates atherosclerosis (establishing that some modified form of LDL is involved); and that knocking out 12/15-lipoxygenase, shown previously to be able to oxidize LDL, ameliorates atherosclerosis.12,15,18–21,28,29 Because the basic pathology and pathogenesis of human atherosclerosis appears to be remarkably similar to that in these animal models, it would be surprising if oxidation were relevant to one and not the other. Why then have the clinical trials to date been mostly negative? One possibility is that oxidation is relevant to atherosclerosis in animal models but not in humans. However, the other possibility is that the design of current clinical trials has not been appropriate for testing the hypothesis.
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Have the Clinical Trials Been Done With the Right Antioxidants at the Right Dosages? |
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Because of a large body of epidemiological data showing a protective role for dietary antioxidants30 and because of the impressive data from experimental studies, a workshop was convened by the National Heart, Blood and Lung Institute in 199131 to review all of the available evidence about the oxidative modification hypothesis. The panel of experts concluded that the evidence was sufficiently strong to justify initiating clinical intervention trials. At the time, the data from trials that used antioxidants in experimental animal models were already quite persuasive, but the field was relatively new and there were many unanswered questions. Just to cite one important example, although OxLDL had been demonstrated in the atherosclerotic lesions of animals and humans, the mechanisms leading to such oxidation were not known and in fact remain unknown to this day.12,15,17,18,29 Nevertheless, the 1991 conferees thought that the use of naturally occurring antioxidants would be safe and that one could therefore proceed even without requiring the kind of in-depth evidence regarding mechanisms that would have been expected if the trials were to be done with drugs. Hence, the recommendations of the committee were to start trials with vitamin E, vitamin C, or ß-carotene. Yet, there was at that time no experimental evidence in animal models that any of these natural antioxidants would have an effect on atherosclerosis. The animal trials available at that time had been carried out mostly with probucol or probucol analogues, and only one study each with diphenylphenylenediamine and butylated hydroxytoluene. What the expert committee was saying, even if not explicitly, was that antioxidants could be looked on as a class of compounds sharing certain common properties and that they would be functionally more or less interchangeable. There may be some justification for such "lumping" when dealing with simple in vitro redox systems, although there are some striking differences. For example, ß-carotene is an excellent trapper of singlet oxygen but much less effective at terminating free radical chain reactions; the reverse is true of vitamin E. In the context of a complex biological system, such "lumping" becomes indefensible. For example, vitamin C is water-soluble, readily absorbed, and transported in the aqueous phase of the plasma; vitamin E is lipid-soluble, poorly absorbed, and transported in lipoproteins. The pharmacodynamics of the various antioxidants differ greatly, and until we know where and how LDL is oxidatively modified in vivo, we have no way to predict which antioxidant, at what dosage and administered by what route, would be most effective.
Vitamin E is the antioxidant used in most of the clinical trials to date. In mouse models of atherosclerosis it has been effective alone32 or in combination with other antioxidants,33,34 but most of the studies in rabbits have been negative.35 Moreover, when administered to humans, vitamin E has been shown to have only a modest inhibitory effect on LDL oxidation ex vivo (delaying copper-induced oxidation by 15 to 20 minutes) but nowhere near the almost complete protection afforded by such a potent antioxidant as probucol (which can delay oxidation for as much as 20 hours). A recent report by Meagher et al36 is highly relevant to this discussion. They fed normal subjects doses of vitamin E ranging from 200 to 2000 mg/d for 8 weeks. The highest dose increased plasma vitamin E levels 5-fold, but urinary excretion of isoprostanes and 4-hydroxynonenal (breakdown products of fatty acid auto-oxidation) was unaffected. The results suggest that in normally nourished subjects, additional vitamin E will not necessarily confer any additional antioxidant protection. Earlier studies in cigarette smokers, in contrast, did show a vitamin E effect on plasma isoprostane levels, suggesting that only in subjects under some oxidative stress will a vitamin E effect be obtained.37 The protective effect of vitamin E against coronary events in the Boaz study7 may reflect the fact that the subjects were under the oxidant stress known to accompany hemodialysis. Moreover, it should be noted that in the absence of an appropriate coantioxidant such as vitamin C, vitamin E can, paradoxically, act as a prooxidant.35 In any case, the available data suggest that vitamin E is not an appropriate antioxidant with which to test the hypothesis in otherwise healthy humans.
Observational data over the years have shown rather consistently that ß-carotene intake is negatively correlated with risk of CHD.30 However, as mentioned above, ß-carotene is not very effective as a chain-breaking antioxidant, compared with vitamin E. Moreover, ß-carotene, even at very high doses, fails to protect circulating LDL against ex vivo oxidation and even fails to protect it in vitro.38–41 Consequently, the trials using ß-carotene are in no sense meaningful tests of the oxidative modification hypothesis.
Clearly, we need more potent antioxidants, possibly with different pharmacodynamic properties. We have much to learn about the very different available antioxidant compounds, how they work, and how they are metabolized.
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The Need for Markers to Assess Whether or Not Oxidation of LDL is Being Successfully Inhibited During a Clinical Trial |
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It is relatively easy to test whether a given antioxidant at a given dosage reaches concentrations sufficient to protect the circulating LDL against oxidation ex vivo. In general, the compounds that have been effective in inhibiting atherosclerosis in animal studies have done so, but the correlation has been far from perfect35,42 and so even this most widely used test cannot be accepted as a satisfactory marker. Other approaches, such as the measurement of urinary or plasma levels of isoprostanes or of hydroperoxides or of OxLDL itself have been suggested. As discussed above, Pratico et al32 showed that vitamin E treatment of apolipoprotein E–deficient mice inhibited atherogenesis. The plasma levels of vitamin E correlated inversely with the extent of lesions and inversely with the urinary excretion, plasma levels, and arterial levels of isoprostanes. Similarly, the titers of autoantibodies to OxLDL correlated directly with the extent of lesions in both LDL receptor-negative and apolipoprotein E–negative mice.43,44 Recently it was shown that the ability of vitamin C to improve the vasodilatory response to acetylcholine could identify patients more likely to have a CHD event.45 If further studies show that these correlations obtain at graded intakes of vitamin E (or other antioxidants) and in other species, they could become examples of the badly needed markers for oxidative stress. So far, none of the candidate markers has been tested in a sufficiently systematic way in animal models to allow them to be used with any confidence as surrogate markers in a clinical trial. Therefore, even if the teams that designed the first generation of human trials had wanted to use a marker, that is, something that would tell them whether or not the antioxidant was "working," they would not have found a tested, reliable method. In fact, with the exception of the Swedish probucol study, in which efficacy was shown with respect to inhibition of LDL oxidation ex vivo,46 none of the reported human trials to date has attempted to assess the efficacy of their antioxidant regimen. Thus, there is no way for us to know whether there was any reason to expect a positive result—there was no independent measure of efficacy. By analogy, it is as if a cholesterol-lowering drug were being tested for efficacy in preventing CHD events but without measurements of plasma cholesterol as part of the protocol. If for no other reason, the results of all of these trials are moot. But there are a number of additional reasons why these trials, however rigorously conducted, have not ruled out the role of oxidative processes in the pathogenesis of human atherosclerosis.
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Identification of Patients Likely to Benefit From Antioxidant Intervention Because of Increased Oxidative Stress |
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In designing clinical trials of hypolipidemic therapy, it was assumed that patients with more marked degrees of hypercholesterolemia would be more likely to show the maximum benefit; therefore, patients with severe hypercholesterolemia were selected. Plasma cholesterol levels were monitored during therapy to document the effectiveness of the given hypolipidemic agent, and the impact on CHD events was correlated to the drop in cholesterol level. However, as noted above, we have no analogous marker to identify patients at high risk because of oxidative stress, that is, patients who would theoretically be expected to benefit most from antioxidant intervention. Equally frustrating is the fact that we have no reliable way to know whether a given antioxidant intervention, whether in patients under oxidative stress or not, effectively reduces the level of oxidant stress. It would seem reasonable that a population under high oxidative stress would stand to benefit the most from antioxidant intervention, and the results of the recently reported Secondary Prevention with Antioxidants of Cardiovascular disease in Endstage renal disease (SPACE) Trial provide some evidence in support of that idea.7 Patients with end-stage kidney disease who were undergoing hemodialysis were randomly assigned to 800 mg/d vitamin E or placebo. End points were myocardial infarction, ischemic stroke, peripheral vascular disease, or unstable angina. This population was chosen because it is well established that patients undergoing chronic hemodialysis are exposed to increased oxidative stress induced by the membranes used in dialysis.47,48 Events were reduced by 54% (P=0.014) and myocardial infarction by 70% (P=0.016). The study was small (n=196), but the results are suggestive. Will other patients under increased oxidative stress, such as diabetics, also constitute a population more likely to benefit from antioxidants? Obviously, biomarkers are urgently needed to identify such high-risk populations and to assess whether therapy effectively lowers the oxidative burden.
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Have the Trials Been Started Early Enough and Have They Lasted Long Enough? |
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The outstanding successes of clinical trials with lipid-lowering regimens led to the almost universal adoption of the canonical 5-year trial. It was natural to settle initially on 5 years as the appropriate duration for trials of antioxidants and, for the same reason, to choose fatal or nonfatal myocardial infarction as primary end points. Yet, the mechanisms by which cholesterol lowering reduces risk could be quite different from the mechanisms by which antioxidants work. For example, the unexpectedly early drop in clinical event rates with intensive cholesterol lowering6 may be caused by mechanisms not shared at all by antioxidants. Furthermore, the animal model studies on which the clinical trials are based do not deal with lesions that cause plaque rupture. Conceivably, the antioxidants might be effective in inhibiting the initial stages of human atherosclerosis, as they are in animals, and yet ineffective or much less effective in reducing plaque instability and rupture. If this were the case, it might be necessary to find some way to assess early stages of lesion development (eg, high resolution ultrasound or MRI) rather than relying on the usual late clinical end points. Of course if the development of early lesions were successfully inhibited, there should eventually be a decrease in the frequency of clinical events, but in that case, the trials might need to extend beyond the conventional 5 years.
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Are There Species Differences Such That the Results in Animal Models Do Not Extrapolate to Humans? |
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Most of the animal model studies demonstrating antioxidant inhibition of atherosclerosis have been done in small animals—rabbits, hamsters, or mice. Only one systematic study has been done in nonhuman primates.49 Is the pathogenesis of the disease in other animal models similar to that in humans? Certainly the morphology is pretty much the same.50–52 There may well be subtle differences, but none has been clearly delineated to date. However, mice and men differ notably with respect to the rate at which they produce free radicals. The rate of free radical generation per unit of body weight is multifold higher in small animals, reflecting their higher metabolic rate; most free radicals are generated within the mitochondria. As discussed above, it is still not known with certainty how oxidation of LDL occurs in vivo, but it is reasonable to assume that it is somehow proportional to the rate of generation of free radical oxygen species (ROS). If so, small animals may always be generating OxLDL at a higher rate than humans and may therefore stand to benefit more than humans from antioxidant treatment. If some threshold value of ROS generation is needed to trigger OxLDL production at a rate that enhances atherogenesis and if ROS generation is below that threshold in humans, then atherosclerosis may develop in normal humans in a manner less sensitive or even totally insensitive to treatment with antioxidants. In addition, hypercholesterolemia per se promotes oxidation13,53 by mechanisms still unclear, and the degree of hypercholesterolemia in animal models far exceeds that seen in human subjects. Still, we know that oxidation of LDL does occur at some rate in humans. Inhibition of that oxidation might prove effective if maintained over a sufficient period of time.
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Summary |
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The lipid hypothesis, despite an overwhelming body of experimental evidence in animal models and epidemiological evidence in humans, was only definitively proved after the development of effective hypolipidemic agents. Similarly, there is now a large body of experimental evidence in animal models and epidemiological data in humans to support the oxidation hypothesis, but effective antioxidant regimens have yet to be developed. With the benefit of hindsight, the decision of the 1991 National Heart, Lung, and Blood Institute workshop to give a green light to trials, even trials that use safe, naturally occurring antioxidants, may have been premature. Not knowing how LDL is oxidized in vivo, we cannot be certain which antioxidants are likely to be most effective. We lack markers that would let us evaluate the efficacy of any given antioxidant intervention, and we lack criteria for rational selection of patients under high oxidative stress. Until we have such basic information, we should put a hold on further clinical trials. Instead, we should concentrate on developing the scientific base that will enable us to design an appropriate trial to test the oxidation hypothesis.
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Acknowledgments |
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The authors are indebted to the National Heart, Lung, and Blood Institute for continuing support of the La Jolla Specialized Center of Research on Molecular Medicine and Atherosclerosis (NHLBI 56989) and to the reviewers of the manuscript for valuable suggestions.
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References |
|---|
1. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996; 334: 1150–1155.
2.
Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996; 334: 1145–1149.
3.
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994; 330: 1029–1035.
4.
Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 154–160.
5. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999; 354: 447–455.[CrossRef][Medline] [Order article via Infotrieve]
6.
Brown BG, Xue-Qiao Z, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001; 345: 1583–1592.
7. Boaz M, Smetana S, Weinstein T, et al. Secondary Prevention with Antioxidants of Cardiovascular disease in Endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet. 2000; 356: 1213–1218.[CrossRef][Medline] [Order article via Infotrieve]
8. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996; 347: 781–785.[CrossRef][Medline] [Order article via Infotrieve]
9. Salonen R, Nyssonen K, Porkkala-Sarataho E, et al. The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. Am J Cardiol. 1995; 76: 34C–39C.[CrossRef][Medline] [Order article via Infotrieve]
10. Mehta J. Intake of antioxidants among American cardiologists. Am J Cardiol. 1997; 79: 1558–1560.[CrossRef][Medline] [Order article via Infotrieve]
11.
Steinberg D. Antioxidant vitamins and coronary heart disease. N Engl J Med. 1993; 328: 1487–1489.Editorial comment.
12. Witztum JL, Steinberg D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc Med. 2001; 11: 93–102.[CrossRef][Medline] [Order article via Infotrieve]
13.
Landmesser U, Harrison DG. Oxidant stress as a marker for cardiovascular events: Ox marks the spot. Circulation. 2001; 104: 2638–2640.
14.
Heinecke JW. Is the emperor wearing clothes? Clinical trials of vitamin E and the LDL oxidation hypothesis. Arterioscler Thromb Vasc Biol. 2001; 21: 1261–1264.
15. Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000; 28: 1815–1826.[CrossRef][Medline] [Order article via Infotrieve]
16. Steinberg D. Is there a potential therapeutic role for vitamin E or other antioxidants in atherosclerosis? Curr Opin Lipidol. 2000; 11: 603–607.[CrossRef][Medline] [Order article via Infotrieve]
17. Parthasarathy S, Khan-Merchant N, Penumetcha M, et al. Do the antioxidant trials fail to validate the oxidation hypothesis? Curr Atheroscler Rep. 2001; 3: 392–398.[Medline] [Order article via Infotrieve]
18. Stocker R. Dietary and pharmacological antioxidants in atherosclerosis. Curr Opin Lipidol. 1999; 10: 589–597.[CrossRef][Medline] [Order article via Infotrieve]
19.
Navab M, Berliner JA, Watson AD, et al. The Yin and Yang of oxidation in the development of the fatty streak: a review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol. 1996; 16: 831–842.
20. Sevanian A, Asatryan L, Ziouzenkova O. Low density lipoprotein (LDL) modification: basic concepts and relationship to atherosclerosis. Blood Purif. 1999; 17: 66–78.[CrossRef][Medline] [Order article via Infotrieve]
21. McCall MR, Frei B. Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radic Biol Med. 1999; 26: 1034–1053.[CrossRef][Medline] [Order article via Infotrieve]
22. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983; 52: 223–261.[CrossRef][Medline] [Order article via Infotrieve]
23.
Goldstein JL, Ho YK, Basu SK, et al. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979; 76: 333–337.
24.
Kodama T, Reddy P, Kishimoto C, et al. Purification and characterization of a bovine acetyl low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1988; 85: 9238–9242.
25. Krieger M, Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994; 63: 601–637.[Medline] [Order article via Infotrieve]
26. Krieger M, Stern DM. Series introduction: multiligand receptors and human disease. J Clin Invest. 2001; 108: 645–647.[CrossRef][Medline] [Order article via Infotrieve]
27.
Steinberg D, Witztum JL. Lipoproteins and atherogenesis: current concepts. JAMA. 1990; 264: 3047–3052.
28. Cyrus T, Witztum JL, Rader D, et al. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999; 103: 1487–1488.[Medline] [Order article via Infotrieve]
29. Heinecke JW. Mechanisms of oxidative damage by myeloperoxidase in atherosclerosis and other inflammatory disorders. J Lab Clin Med. 1999; 133: 321–325.[CrossRef][Medline] [Order article via Infotrieve]
30.
Jha P, Flather M, Lonn E, et al. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med. 1995; 123: 860–872.
31.
Steinberg D. Antioxidants in the prevention of human atherosclerosis: summary of the proceedings of a National Heart, Lung, and Blood Institute Workshop: September 5–6, 1991, Bethesda, Maryland. Circulation. 1992; 85: 2337–2344.
32. Pratico D, Tangirala R, Rader D, et al. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med. 1999; 10: 1189–1192.
33.
Thomas SR, Leichtweis SB, Pettersson K, et al. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001; 21: 585–593.
34.
Crawford RS, Kirk EA, Rosenfeld ME, et al. Dietary antioxidants inhibit development of fatty streak lesions in the LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol. 1998; 18: 1506–1513.
35. Stocker R. The ambivalence of vitamin E in atherogenesis. Trends Biochem Sci. 1999; 24: 219–223.[CrossRef][Medline] [Order article via Infotrieve]
36.
Meagher EA, Barry OP, Lawson JA, et al. Effects of vitamin E on lipid peroxidation in healthy persons. JAMA. 2001; 285: 1178–1182.
37.
Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers: smoking as a cause of oxidative damage. N Engl J Med. 1995; 332: 1198–1203.
38.
Reaven P, Khouw A, Beltz W, et al. Effect of dietary antioxidant combinations in humans: protection of LDL by vitamin E, but not by B-carotene. Arterioscler Thromb. 1993; 13: 590–600.
39. Witztum JL, Reaven PD, Parthasarathy S. Studies on the ability of dietary supplementation with B-carotene to protect low density lipoprotein from oxidative modification. Ann N Y Acad Sci. 1994; 691: 200–206.
40.
Reaven PD, Ferguson E, Navab ,M, et al. Susceptibility of human LDL to oxidative modification: effects of variations in beta-carotene concentration and oxygen tension. Arterioscler Thromb. 1994; 14: 1162–1169.
41. Gaziano J, Hatta A, Flynn M, et al. Supplementation with B-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation. Atherosclerosis. 1995; 112: 187–195.[CrossRef][Medline] [Order article via Infotrieve]
42. Fruebis J, Bird D, Pattison J, et al. The extent of antioxidant protection of plasma low density lipoprotein (LDL) is not a predictor of the antiatherogenic effect of antioxidants in LDL receptor deficient rabbits. J Lipid Res. 1997; 38: 2455–2464.[Abstract]
43.
Tsimikas S, Palinski W, Witztum JL. Circulating autoantibodies to oxidized LDL correlate with arterial accumulation and depletion of oxidized LDL in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21: 95–100.
44.
Cyrus T, Pratico D, Zhao L, et al. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation;. 2001; 103: 2277–2282.
45.
Heitzer T, Schlinzig T, Krohn K, et al. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001; 104: 2673–2678.
46. Walldius G, Erikson U, Olsson AG, et al. The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol. 1994; 74: 875–883.[CrossRef][Medline] [Order article via Infotrieve]
47. Loughrey CM, Young IS, McEneny J, et al. Oxidation of low density lipoprotein in patients on regular haemodialysis. Atherosclerosis. 1994; 110: 185–193.[CrossRef][Medline] [Order article via Infotrieve]
48. Boaz M, Matas Z, Biro A, et al. Serum malondialdehyde and prevalent cardiovascular disease in hemodialysis. Kidney Int. 1999; 56: 1078–1083.[CrossRef][Medline] [Order article via Infotrieve]
49. Sasahara M, Raines EW, Carew TE, et al. Inhibition of hypercholesterolemia-induced atherosclerosis in Macada Nemestrina by probucol, I: intimal lesion area correlates inversely with resistance of lipoproteins to oxidation. J Clin Invest. 1994; 94: 155–164.
50.
Nakashima Y, Plump AS, Raines EW, et al. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994; 14: 133–140.
51. Ross R, Agius L. The process of atherogenesis–cellular and molecular interaction: from experimental animal models to humans. Diabetologia. 1992; 35 (suppl 2): S34–S40.
52. Tsukada T, Rosenfeld M, Ross R, et al. Immunocytochemical analysis of cellular components in atherosclerotic lesions: use of monoclonal antibodies with the Watanabe and fat-fed rabbit. Arteriosclerosis. 1986; 6: 601–613.[Abstract]
53. Harrison DG, Ohara Y. Physiological consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: implications for impaired vasomotion. Am J Cardiol. 1995; 75: 75B-81B.[CrossRef][Medline] [Order article via Infotrieve]
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 F. M. Nakhoul, R. Miller-Lotan, H. Awad, R. Asleh, K. Jad, N. Nakhoul, R. Asaf, N. Abu-Saleh, and A. P. Levy Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus Am J Physiol Renal Physiol, April 1, 2009; 296(4): F830 - F838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Steinberg The LDL modification hypothesis of atherogenesis: an update J. Lipid Res., April 1, 2009; 50(Supplement): S376 - S381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. N. Hodis, W. J. Mack, L. Dustin, P. R. Mahrer, S. P. Azen, R. Detrano, J. Selhub, P. Alaupovic, C.-r. Liu, C.-h. Liu, et al. High-Dose B Vitamin Supplementation and Progression of Subclinical Atherosclerosis: A Randomized Controlled Trial Stroke, March 1, 2009; 40(3): 730 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kato, C. Mori, K. Kitazato, S. Arata, T. Obama, M. Mori, K. Takahashi, T. Aiuchi, T. Takano, and H. Itabe Transient Increase in Plasma Oxidized LDL During the Progression of Atherosclerosis in Apolipoprotein E Knockout Mice Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 33 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Juarez-Rojas, A. Medina-Urrutia, R Posadas-Sanchez, E Jorge-Galarza, E Mendoza-Perez, N Caracas-Portilla, G Cardoso-Saldana, G Munoz-Gallegos, and C Posadas-Romero High-density lipoproteins are abnormal in young women with uncomplicated systemic lupus erythematosus Lupus, November 1, 2008; 17(11): 981 - 987. [Abstract] [PDF]
|
|
|
|
 |
|
 A.-L. Levonen, E. Vahakangas, J. K. Koponen, and S. Yla-Herttuala Antioxidant Gene Therapy for Cardiovascular Disease: Current Status and Future Perspectives Circulation, April 22, 2008; 117(16): 2142 - 2150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Gusdon, T. V. Votyakova, and C. E. Mathews mt-Nd2a Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III J. Biol. Chem., April 18, 2008; 283(16): 10690 - 10697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Walter, R. F. Jacob, R. E. Bjork, B. Jeffers, J. Buch, Y. Mizuno, R. P. Mason, and on behalf of the PREVENT Investigators Circulating Lipid Hydroperoxides Predict Cardiovascular Events in Patients With Stable Coronary Artery Disease: The PREVENT Study J. Am. Coll. Cardiol., March 25, 2008; 51(12): 1196 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Blum, U. Milman, C. Shapira, R. Miller-Lotan, L. Bennett, M. Kostenko, M. Landau, S. Keidar, Y. Levy, A. Khemlin, et al. Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): e18 - e20. [Full Text] [PDF]
|
|
|
|
|
|
U. Milman, S. Blum, C. Shapira, D. Aronson, R. Miller-Lotan, Y. Anbinder, J. Alshiek, L. Bennett, M. Kostenko, M. Landau, et al. Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2-2 Genotype: A Prospective Double-Blinded Clinical Trial Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 341 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Cangemi, L. Loffredo, R. Carnevale, L. Perri, M. P. Patrizi, V. Sanguigni, P. Pignatelli, and F. Violi Early decrease of oxidative stress by atorvastatin in hypercholesterolaemic patients: effect on circulating vitamin E Eur. Heart J., January 1, 2008; 29(1): 54 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lu, W. Jiang, J.-H. Yang, P.-Y. Chang, J. P. Walterscheid, H.-H. Chen, M. Marcelli, D. Tang, Y.-T. Lee, W. S.L. Liao, et al. Electronegative LDL Impairs Vascular Endothelial Cell Integrity in Diabetes by Disrupting Fibroblast Growth Factor 2 (FGF2) Autoregulation Diabetes, January 1, 2008; 57(1): 158 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Siekmeier, C. Steffen, and W. Marz Role of Oxidants and Antioxidants in Atherosclerosis: Results of In Vitro and In Vivo Investigations Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2007; 12(4): 265 - 282. [Abstract] [PDF]
|
|
|
|
|
|
C. R. Stewart, A. Haw III, R. Lopez, T. O. McDonald, J. M. Callaghan, M. J. McConville, K. J. Moore, G. J. Howlett, and K. D. O'Brien Serum amyloid P colocalizes with apolipoproteins in human atheroma: functional implications J. Lipid Res., October 1, 2007; 48(10): 2162 - 2171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wen and D. S. Leake Low Density Lipoprotein Undergoes Oxidation Within Lysosomes in Cells Circ. Res., May 11, 2007; 100(9): 1337 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Ignarro, M. L. Balestrieri, and C. Napoli Nutrition, physical activity, and cardiovascular disease: An update Cardiovasc Res, January 15, 2007; 73(2): 326 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. Dzau, E. M. Antman, H. R. Black, D. L. Hayes, J. E. Manson, J. Plutzky, J. J. Popma, and W. Stevenson The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease) Circulation, December 19, 2006; 114(25): 2850 - 2870. [Full Text] [PDF]
|
|
|
|
|
|
M. Mastorikou, M. Mackness, and B. Mackness Defective Metabolism of Oxidized Phospholipid by HDL From People With Type 2 Diabetes Diabetes, November 1, 2006; 55(11): 3099 - 3103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Bleys, E. R Miller III, R. Pastor-Barriuso, L. J Appel, and E. Guallar Vitamin-mineral supplementation and the progression of atherosclerosis: a meta-analysis of randomized controlled trials. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 880 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Napoli, S. Williams-Ignarro, F. de Nigris, L. O. Lerman, F. P. D'Armiento, E. Crimi, R. E. Byrns, A. Casamassimi, A. Lanza, F. Gombos, et al. Physical training and metabolic supplementation reduce spontaneous atherosclerotic plaque rupture and prolong survival in hypercholesterolemic mice PNAS, July 5, 2006; 103(27): 10479 - 10484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Stranges, J. R. Marshall, M. Trevisan, R. Natarajan, R. P. Donahue, G. F. Combs, E. Farinaro, L. C. Clark, and M. E. Reid Effects of Selenium Supplementation on Cardiovascular Disease Incidence and Mortality: Secondary Analyses in a Randomized Clinical Trial Am. J. Epidemiol., April 15, 2006; 163(8): 694 - 699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Mason, M. F. Walter, C. A. Day, and R. F. Jacob Active Metabolite of Atorvastatin Inhibits Membrane Cholesterol Domain Formation by an Antioxidant Mechanism J. Biol. Chem., April 7, 2006; 281(14): 9337 - 9345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. DeMaio, M. Rouhanizadeh, S. Reddy, A. Sevanian, J. Hwang, and T. K. Hsiai Oxidized phospholipids mediate occludin expression and phosphorylation in vascular endothelial cells Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H674 - H683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Steinberg Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia J. Lipid Res., October 1, 2005; 46(10): 2037 - 2051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E. Freeman, A. E. Rusinol, M. Linton, D. L. Hachey, S. Fazio, M. S. Sinensky, and D. Thewke Acyl-coenzyme A:cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages J. Lipid Res., September 1, 2005; 46(9): 1933 - 1943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hayashida, N. Kume, T. Murase, M. Minami, D. Nakagawa, T. Inada, M. Tanaka, A. Ueda, G. Kominami, H. Kambara, et al. Serum Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels Are Elevated in Acute Coronary Syndrome: A Novel Marker for Early Diagnosis Circulation, August 9, 2005; 112(6): 812 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Durga, L. J. H. van Tits, E. G. Schouten, F. J. Kok, and P. Verhoef Effect of Lowering of Homocysteine Levels on Inflammatory Markers: A Randomized Controlled Trial Arch Intern Med, June 27, 2005; 165(12): 1388 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mohn, M. Catino, R. Capanna, C. Giannini, M. Marcovecchio, and F. Chiarelli Increased Oxidative Stress in Prepubertal Severely Obese Children: Effect of a Dietary Restriction-Weight Loss Program J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2653 - 2658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The HOPE and HOPE-TOO Trial Investigators Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial JAMA, March 16, 2005; 293(11): 1338 - 1347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Torzewski, P. X. Shaw, K.-R. Han, B. Shortal, K. J. Lackner, J. L. Witztum, W. Palinski, and S. Tsimikas Reduced In Vivo Aortic Uptake of Radiolabeled Oxidation-Specific Antibodies Reflects Changes in Plaque Composition Consistent With Plaque Stabilization Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2307 - 2312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Walter, R. F. Jacob, B. Jeffers, M. M. Ghadanfar, G. M. Preston, J. Buch, and R. P. Mason Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease: A longitudinal analysis of the PREVENT study J. Am. Coll. Cardiol., November 16, 2004; 44(10): 1996 - 2002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Van Lenten, A. C. Wagner, M. Navab, G.M. Anantharamaiah, E. K.-W. Hui, D. P. Nayak, and A. M. Fogelman D-4F, an Apolipoprotein A-I Mimetic Peptide, Inhibits the Inflammatory Response Induced by Influenza A Infection of Human Type II Pneumocytes Circulation, November 16, 2004; 110(20): 3252 - 3258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-Y. Chang, S.-C. Lu, T.-C. Su, S.-F. Chou, W.-H. Huang, J. D. Morrisett, C.-H. Chen, C.-S. Liau, and Y.-T. Lee Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation J. Lipid Res., November 1, 2004; 45(11): 2116 - 2122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schneider, B. Verges, A. Klein, E. R. Miller, V. Deckert, C. Desrumaux, D. Masson, P. Gambert, J.-M. Brun, J. Fruchart-Najib, et al. Alterations in Plasma Vitamin E Distribution in Type 2 Diabetic Patients With Elevated Plasma Phospholipid Transfer Protein Activity Diabetes, October 1, 2004; 53(10): 2633 - 2639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Kris-Etherton, A. H. Lichtenstein, B. V. Howard, D. Steinberg, J. L. Witztum, and for the Nutrition Committee of the American Heart Antioxidant Vitamin Supplements and Cardiovascular Disease Circulation, August 3, 2004; 110(5): 637 - 641. [Full Text] [PDF]
|
|
|
|
|
|
A. Kontush, M. J. Chapman, and R. Stocker Vitamin E Is Not Deficient in Human Atherosclerotic Plaques Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): e139 - e140. [Full Text] [PDF]
|
|
|
|
|
|
R. Carmena, P. Duriez, and J.-C. Fruchart Atherogenic Lipoprotein Particles in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-2 - III-7. [Abstract] [Full Text]
|
|
|
|
|
|
R. Paoletti, A. M. Gotto Jr, and D. P. Hajjar Inflammation in Atherosclerosis and Implications for Therapy Circulation, June 15, 2004; 109(23_suppl_1): III-20 - III-26. [Abstract] [Full Text]
|
|
|
|
|
|
J. Davignon and P. Ganz Role of Endothelial Dysfunction in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-27 - III-32. [Abstract] [Full Text]
|
|
|
|
|
|
C. Napoli, S. Williams-Ignarro, F. de Nigris, L. O. Lerman, L. Rossi, C. Guarino, G. Mansueto, F. Di Tuoro, O. Pignalosa, G. De Rosa, et al. Long-term combined beneficial effects of physical training and metabolic treatment on atherosclerosis in hypercholesterolemic mice PNAS, June 8, 2004; 101(23): 8797 - 8802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F Violi, L Loffredo, L Musella, and A Marcoccia Should antioxidant status be considered in interventional trials with antioxidants? Heart, June 1, 2004; 90(6): 598 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-Y. Chyu, S. M. Babbidge, X. Zhao, R. Dandillaya, A. G. Rietveld, J. Yano, P. Dimayuga, B. Cercek, and P. K. Shah Differential Effects of Green Tea-Derived Catechin on Developing Versus Established Atherosclerosis in Apolipoprotein E-Null Mice Circulation, May 25, 2004; 109(20): 2448 - 2453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Levy, P. Friedenberg, R. Lotan, P. Ouyang, M. Tripputi, L. Higginson, F. R. Cobb, J.-C. Tardif, V. Bittner, and B. V. Howard The Effect of Vitamin Therapy on the Progression of Coronary Artery Atherosclerosis Varies by Haptoglobin Type in Postmenopausal Women Diabetes Care, April 1, 2004; 27(4): 925 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Reiterer, M. Toborek, and B. Hennig Quercetin Protects Against Linoleic Acid-Induced Porcine Endothelial Cell Dysfunction J. Nutr., April 1, 2004; 134(4): 771 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Ryoo, D.-U. Kim, M. Won, K.-S. Chung, Y.-J. Jang, G.-T. Oh, S.-K. Park, P.-J. Maeng, H.-S. Yoo, and K.-L. Hoe Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells Cardiovasc Res, April 1, 2004; 62(1): 185 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Medeiros, T. Khan, J. B. El Khoury, C. L. L. Pham, D. M. Hatters, G. J. Howlett, R. Lopez, K. D. O'Brien, and K. J. Moore Fibrillar Amyloid Protein Present in Atheroma Activates CD36 Signal Transduction J. Biol. Chem., March 12, 2004; 279(11): 10643 - 10648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shimada, H. Mokuno, E. Matsunaga, T. Miyazaki, K. Sumiyoshi, A. Kume, K. Miyauchi, and H. Daida Predictive Value of Circulating Oxidized LDL for Cardiac Events in Type 2 Diabetic Patients With Coronary Artery Disease Diabetes Care, March 1, 2004; 27(3): 843 - 844. [Full Text] [PDF]
|
|
|
|
|
|
F. Micheletta, S. Natoli, M. Misuraca, E. Sbarigia, U. Diczfalusy, and L. Iuliano Vitamin E Supplementation in Patients With Carotid Atherosclerosis: Reversal of Altered Oxidative Stress Status in Plasma but not in Plaque Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 136 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hwang, M. H. Ing, A. Salazar, B. Lassegue, K. Griendling, M. Navab, A. Sevanian, and T. K. Hsiai Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation Circ. Res., December 12, 2003; 93(12): 1225 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part II: Animal and Human Studies Circulation, October 28, 2003; 108(17): 2034 - 2040. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Blankenberg, H. J. Rupprecht, C. Bickel, M. Torzewski, G. Hafner, L. Tiret, M. Smieja, F. Cambien, J. Meyer, K. J. Lackner, et al. Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients with Coronary Artery Disease N. Engl. J. Med., October 23, 2003; 349(17): 1605 - 1613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Hak, M. J. Stampfer, H. Campos, H. D. Sesso, J. M. Gaziano, W. Willett, and J. Ma Plasma Carotenoids and Tocopherols and Risk of Myocardial Infarction in a Low-Risk Population of US Male Physicians Circulation, August 19, 2003; 108(7): 802 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Palinski United They Go: Conjunct Regulation of Aortic Antioxidant Enzymes During Atherogenesis Circ. Res., August 8, 2003; 93(3): 183 - 185. [Full Text] [PDF]
|
|
|
|
|
|
C. Holmquist, S. Larsson, A. Wolk, and U. de Faire Multivitamin Supplements Are Inversely Associated with Risk of Myocardial Infarction in Men and Women--Stockholm Heart Epidemiology Program (SHEEP) J. Nutr., August 1, 2003; 133(8): 2650 - 2654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Shishehbor, M.-L. Brennan, R. J. Aviles, X. Fu, M. S. Penn, D. L. Sprecher, and S. L. Hazen Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways Circulation, July 29, 2003; 108(4): 426 - 431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Stenvinkel, R. Pecoits-Filho, and B. Lindholm Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1927 - 1939. [Full Text] [PDF]
|
|
|
|
|
|
R. Asleh, S. Marsh, M. Shilkrut, O. Binah, J. Guetta, F. Lejbkowicz, B. Enav, N. Shehadeh, Y. Kanter, O. Lache, et al. Genetically Determined Heterogeneity in Hemoglobin Scavenging and Susceptibility to Diabetic Cardiovascular Disease Circ. Res., June 13, 2003; 92(11): 1193 - 1200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Redon, M. R. Oliva, C. Tormos, V. Giner, J. Chaves, A. Iradi, and G. T. Saez Antioxidant Activities and Oxidative Stress Byproducts in Human Hypertension Hypertension, May 1, 2003; 41(5): 1096 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Chen, T. Jiang, J.-H. Yang, W. Jiang, J. Lu, G. K. Marathe, H. J. Pownall, C. M. Ballantyne, T. M. McIntyre, P. D. Henry, et al. Low-Density Lipoprotein in Hypercholesterolemic Human Plasma Induces Vascular Endothelial Cell Apoptosis by Inhibiting Fibroblast Growth Factor 2 Transcription Circulation, April 29, 2003; 107(16): 2102 - 2108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gotto Jr Antioxidants, statins, and atherosclerosis J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1205 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z S Nedeljkovic, N Gokce, and J Loscalzo Mechanisms of oxidative stress and vascular dysfunction Postgrad. Med. J., April 1, 2003; 79(930): 195 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. de Nigris, L. O. Lerman, S. W. Ignarro, G. Sica, A. Lerman, W. Palinski, L. J. Ignarro, and C. Napoli From the Cover: Beneficial effects of antioxidants and L-arginine on oxidation-sensitive gene expression and endothelial NO synthase activity at sites of disturbed shear stress PNAS, February 4, 2003; 100(3): 1420 - 1425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Landmesser and H. Drexler Oxidative stress, the renin-angiotensin system, and atherosclerosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A3 - A7. [Abstract] [PDF]
|
|
|
|
|
|
F. Violi, F. Micheletta, L. Iuliano, D. Steinberg, and J. L. Witztum How to Select Patient Candidates for Antioxidant Treatment? * Response Circulation, December 10, 2002; 106 (24): e195 - e195. [Full Text] [PDF]
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