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• W1996954911 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 24, No. 7Vitamin E Is Not Deficient in Human Atherosclerotic Plaques Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBVitamin E Is Not Deficient in Human Atherosclerotic Plaques Anatol Kontush and M. John Chapman Roland Stocker Anatol KontushAnatol Kontush Dyslipoproteinemia and Atherosclerosis Research Unit (U.551), National Institute for Health and Medical Research (INSERM), Paris, France Search for more papers by this author and M. John ChapmanM. John Chapman Dyslipoproteinemia and Atherosclerosis Research Unit (U.551), National Institute for Health and Medical Research (INSERM), Paris, France Search for more papers by this author Roland StockerRoland Stocker Centre for Vascular Research, University of New South Wales, Department of Haematology, Prince of Wales Hospital, Sydney, Australia Search for more papers by this author Originally published1 Jul 2004https://doi.org/10.1161/01.ATV.0000131259.97572.99Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e139–e140To the Editor:With great interest, we recently read the article entitled “Vitamin E supplementation in patients with carotid atherosclerosis: reversal of altered oxidative stress status in plasma but not in plaque” published in the January 2004 issue of Arterioscler Thromb Vasc Biol.1 This article addresses the endogenous vitamin E status of candidates for carotid endarterectomy as compared with healthy controls and evaluates the effect of supplemental vitamin E on markers of oxidative stress in the circulation and in atherosclerotic plaques. These questions are important in light of several large-scale clinical trials documenting a lack of benefit of dietary vitamin E supplementation relative to the risk of coronary heart disease2–4 (reviewed by Kritharides et al5). The authors reported plasma vitamin E/cholesterol ratios to be lower in patients than in controls, and 7β-hydroxycholesterol/vitamin E ratios to be substantially higher in carotid plaque than plasma.1 Based on these findings, the authors concluded “vitamin E levels are reduced in… atherosclerotic plaques of patients with advanced atherosclerosis.”1In our opinion, this conclusion is not justified, for the following reasons. First, it is based on comparison of vitamin E/cholesterol ratios in plaques versus control plasma1 (Table). Second, 7β-hydroxycholesterol/vitamin E ratios reflect the extent of cholesterol oxidation relative to the concentration of the vitamin, so that changes in either or both compound(s) affect the ratio. Analysis of the data reported1 clearly shows that higher levels of 7β-hydroxycholesterol (330±170 versus 2.1±0.4 nmol/mmol cholesterol for plaque and plasma, respectively) rather than lower concentrations of vitamin E (2.06±0.7 versus 3.05±0.6 μmol/mmol cholesterol for plaque and plasma, respectively) are responsible for the difference in the 7β-hydroxycholesterol/vitamin E ratios. Third, the authors’ data in fact show that the concentrations of vitamin E in plaques and normal vessels are comparable (2.06±0.7 versus 0.54±0.3 μmol/mmol cholesterol for plaques and normal vessels, respectively)1 (Table). Indeed, the lack of a deficit in α-tocopherol in human atherosclerotic plaques has been documented previously (Table).6–8 Moreover, the intra-plaque levels of α-tocopherol do not differ between early, intermediate, and advanced lesions and are comparable to plasma levels of the vitamin (Table).6,8,9 Similar results have been reported for the vitamin E content of lipoproteins isolated from human lesions corresponding to different developmental stages.9,10 In addition, gas chromatography–mass spectrometry analysis suggests that only a fraction (<20%) of vitamin E is oxidized in the lesions.9 Thus, the data of Micheletta at el1 and others6–10 have consistently documented the absence of a deficit of vitamin E in human plaque tissue, even at advanced stages of atherosclerosis. Lipid-Adjusted Concentrations of Vitamin E in Arterial Tissue and Plasma from Atherosclerotic Patients and Control SubjectsAtherosclerotic PatientsControlsArteryAtherosclerosisP for the DifferenceReferenceNumerical data is given in μmol/mmol cholesterol unless indicated otherwise.*Recalculated using a molar ratio of total cholesterol/free cholesterol of 1.76.6†Data shown are representative of 29 studies on plasma levels of vitamin E in atherosclerosis found in Medline (14 of which show a decrease in the vitamin E in atherosclerosis and 15 do not).‡μmol/mmol cholesterol+triglycerides.P indicates patients; C, controls.Arterial tissue2.1±0.70.5±0.3Carotid (P), thoracic (C)AdvancedNS13.6±2.7*2.4±1.0*Carotid, femoral (P), iliac (C)AdvancedNS66.3±2.5CarotidAdvanced94.8±2.2AortaInitial lesions74.9±0.8AortaFatty streaks75.4±1.6AortaFibro-fatty lesions72.0±1.9AortaComplex lesions7Plasma†3.0±0.66.3±1.7Advanced<0.00111.9±0.6‡2.3±0.5‡Myocardial infarction<0.001113.5±1.62.8±0.9Coronary heart diseaseNS154.1±1.24.8±1.3Peripheral vascular diseaseNS16It is also relevant that a decrease in plasma vitamin E levels in atherosclerotic patients versus controls, as reported by Micheletta at el,1 is not observed consistently. For example, lipid-adjusted plasma levels of vitamin E have been reported to be lower in subjects with myocardial infarction as compared with their respective controls.11,12 By contrast, patients with advanced atherosclerosis,13 unstable coronary syndrome,14 coronary heart disease,15 peripheral vascular disease,16 or hyperlipidemia17 were reported to display normal plasma vitamin E levels (Table).Interestingly, Micheletta at el.1 reported that supplementation of candidates for carotid endarterectomy with α-tocopherol (450 IU/d for 6 weeks) led to elevation in its concentration in plasma but not in carotid plaques. The reasons for this difference are not clear at present. Based on the observed increased circulating concentrations of α-tocopherol,1 and the fact that the vitamin is transported by and enters the vessel wall via lipoproteins, one might expect lesion vitamin E levels to increase with increasing severity of the disease in subjects displaying atherogenic dyslipidemia. However, at advanced stages of plaque development, accumulation of lipoprotein-derived lipids and antioxidants may no longer be substantial, particularly over the relatively short period of six weeks examined,1 or vitamin E may be metabolized faster than (and independently of) lipoprotein-derived lipids. Regarding the latter possibility, it is known that oxidation does not appear to contribute significantly to a putative increase in metabolism of vitamin E in endarterectomy specimens.8 In any case, the findings of Micheletta et al1 suggest that supplemental vitamin E may not have reached its target tissue, and that plasma α-tocopherol is not a suitable surrogate measure for vessel wall vitamin E.Concomitant with the increased plasma concentration of α-tocopherol, 7β-hydroxycholesterol levels decreased in plasma but not in lesions. The authors concluded that α-tocopherol supplementation beneficially influenced oxidative stress in plasma but not in atherosclerotic plaques. The apparent inability of therapeutic amounts of supplemental vitamin E to decrease oxidative stress in human atherosclerotic lesions is consistent with earlier studies (reviewed by Upston et al18) and with the observation that vitamin E is not deficient in human lesions.1,6–8 In contrast, much higher pharmacological doses of the vitamin have been reported to decrease both aortic lipid oxidation and lesion formation in some19 but not all20 animal studies (see Neuzil et al21 and Upston et al22 for review).The study by Micheletta at el1 confirms previous reports6,8,9 that atherosclerotic lesions contain elevated levels of oxidized lipids as compared with that in normal arteries and plasma (reviewed by Upston et al18). Therefore, the available data suggests that in diseased vessels, oxidation of lipids, including those in lipoproteins, occurs in the presence of α-tocopherol.8,18 Mechanistically, such oxidation can be explained readily by the model of tocopherol-mediated peroxidation.23Oxidative stress is believed to play a key role in the initiation and progression of atherosclerosis, and supplementation with antioxidants is believed to beneficially influence the disease.24 Quantitatively, α-tocopherol is the major antioxidant in organic extracts of LDL,25 and it is therefore not surprising that it was first chosen for large-scale clinical trials.2–4 However, there is accumulating evidence to suggest a major role for two-electron oxidants (such as hypochlorite and peroxynitrite) in lipoprotein oxidation and in other oxidative events in the arterial wall.9,18,26 Importantly, α-tocopherol does not provide protection against these oxidants.27,28 Rather than casting doubt on the concept that antioxidants may be beneficial in the treatment of atherosclerosis, these findings shift attention from vitamin E to agents that could provide protection against physiologically relevant oxidants. The latter may include HDL-associated proteins,29,30 such as those whose precise mechanism of action and relevance to atherosclerosis deserve detailed investigation.1 Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U, Iuliano L. Vitamin E supplementation in patients with carotid atherosclerosis: reversal of altered oxidative stress status in plasma but not in plaque. Arterioscler Thromb Vasc Biol. 2004; 24: 136–140.LinkGoogle Scholar2 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.CrossrefMedlineGoogle Scholar3 Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. 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.CrossrefMedlineGoogle Scholar4 Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang J, Selzer RH, Azen SP. α-Tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002; 106: 1453–1459.LinkGoogle Scholar5 Kritharides L, Stocker R. The use of antioxidant supplements in coronary heart disease. Atherosclerosis. 2002; 164: 211–219.CrossrefMedlineGoogle Scholar6 Suarna C, Dean RT, May J, Stocker R. Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of α-tocopherol and ascorbate. Arterioscler Thromb Vasc Biol. 1995; 15: 1616–1624.CrossrefMedlineGoogle Scholar7 Upston JM, Niu X, Brown AJ, Mashima R, Wang H, Senthilmohan R, Kettle AJ, Dean RT, Stocker R. Disease stage-dependent accumulation of lipid and protein oxidation products in human atherosclerosis. Am J Pathol. 2002; 160: 701–710.CrossrefMedlineGoogle Scholar8 Upston JM, Terentis AC, Morris K, Keaney Jr JF, Stocker R. Oxidized lipid accumulates in the presence of α-tocopherol in atherosclerosis. Biochem J. 2002; 363: 753–760.CrossrefMedlineGoogle Scholar9 Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. Vitamin E oxidation in human atherosclerotic lesions. Circ Res. 2002; 90: 333–339.CrossrefMedlineGoogle Scholar10 Niu X, Zammit V, Upston JM, Dean RT, Stocker R. Coexistence of oxidized lipids and α-tocopherol in all lipoprotein density fractions isolated from advanced human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 1999; 19: 1708–1718.CrossrefMedlineGoogle Scholar11 Regnstrom J, Nilsson J, Moldeus P, Strom K, Bavenholm P, Tornvall P, Hamsten A. Inverse relation between the concentration of low-density-lipoprotein vitamin E and severity of coronary artery disease. Am J Clin Nutr. 1996; 63: 377–385.CrossrefMedlineGoogle Scholar12 Ruiz Rejon F, Martin Pena G, Lopez Manglano C, Seijas Martinez V, Ruiz Galiana J. [Plasma levels of vitamins A and E and the risk of acute myocardial infarct]. Rev Clin Esp. 1997; 197: 411–416.(In Spanish)MedlineGoogle Scholar13 Cleary J, Mohr D, Adams MR, Celermajer DS, Stocker R. Plasma and LDL levels of major lipophilic antioxidants are similar in patients with advanced atherosclerosis and age-matched controls. Free Radic Res. 1997; 26: 175–182.CrossrefMedlineGoogle Scholar14 Vita JA, Keaney JF Jr, Raby KE, Morrow JD, Freedman JE, Lynch S, Koulouris SN, Hankin BR, Frei B. Low plasma ascorbic acid independently predicts the presence of an unstable coronary syndrome. J Am Coll Cardiol. 1998; 31: 980–986.CrossrefMedlineGoogle Scholar15 Kontush A, Spranger T, Reich A, Baum K, Beisiegel U. Lipophilic antioxidants in blood plasma as markers of atherosclerosis: the role of α-carotene and γ-tocopherol. Atherosclerosis. 1999; 144: 117–122.MedlineGoogle Scholar16 Sanderson KJ, van Rij AM, Wade CR, Sutherland WH. Lipid peroxidation of circulating low density lipoproteins with age, smoking and in peripheral vascular disease. Atherosclerosis. 1995; 118: 45–51.CrossrefMedlineGoogle Scholar17 Kontush A, Reich A, Baum K, Spranger T, Finckh B, Kohlschutter A, Beisiegel U. Plasma ubiquinol-10 is decreased in patients with hyperlipidaemia. Atherosclerosis. 1997; 129: 119–126.CrossrefMedlineGoogle Scholar18 Upston JM, Kritharides L, Stocker R. The role of vitamin E in atherosclerosis. Prog Lipid Res. 2003; 42: 405–422.CrossrefMedlineGoogle Scholar19 Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med. 1998; 4: 1189–1192.CrossrefMedlineGoogle Scholar20 Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. 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.CrossrefMedlineGoogle Scholar21 Neuzil J, Weber C, Kontush A. The role of vitamin E in atherogenesis: linking the chemical, biological and clinical aspects of the disease. Atherosclerosis. 2001; 157: 257–283.CrossrefMedlineGoogle Scholar22 Upston JM, Terentis AC, Stocker R. Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement. FASEB J. 1999; 13: 977–994.CrossrefMedlineGoogle Scholar23 Bowry VW, Stocker R. Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J Am Chem Soc. 1993; 115: 6029–6044.CrossrefGoogle Scholar24 Steinberg D, Witztum JL. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation. 2002; 105: 2107–2111.LinkGoogle Scholar25 Esterbauer H, Gebicki J, Puhl H, Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med. 1992; 13: 341–390.CrossrefMedlineGoogle Scholar26 Gaut JP, Heinecke JW. Mechanisms for oxidizing low-density lipoprotein. Insights from patterns of oxidation products in the artery wall and from mouse models of atherosclerosis. Trends Cardiovasc Med. 2001; 11: 103–112.CrossrefMedlineGoogle Scholar27 Hazell LJ, Stocker R. α-Tocopherol does not inhibit hypochlorite-induced oxidation of apolipoprotein B-100 of low-density lipoprotein. FEBS Lett. 1997; 414: 541–544.CrossrefMedlineGoogle Scholar28 Thomas SR, Davies MJ, Stocker R. Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite. Chem Res Toxicol. 1998; 11: 484–494.CrossrefMedlineGoogle Scholar29 Van Lenten BJ, Navab M, Shih D, Fogelman AM, Lusis AJ. The role of high-density lipoproteins in oxidation and inflammation. Trends Cardiovasc Med. 2001; 11: 155–161.CrossrefMedlineGoogle Scholar30 Kontush A, Chantepie S, Chapman MJ. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. Arterioscler Thromb Vasc Biol. 2003; 23: 1881–1888.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Godzien J, Ciborowski M, Armitage E, Jorge I, Camafeita E, Burillo E, Martín-Ventura J, Rupérez F, Vázquez J and Barbas C (2016) A Single In-Vial Dual Extraction Strategy for the Simultaneous Lipidomics and Proteomics Analysis of HDL and LDL Fractions, Journal of Proteome Research, 10.1021/acs.jproteome.5b00898, 15:6, (1762-1775), Online publication date: 3-Jun-2016. Azzi A (2007) Oxidative stress: A dead end or a laboratory hypothesis?, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2007.07.124, 362:2, (230-232), Online publication date: 1-Oct-2007. Singh U, Devaraj S and Jialal I (2005) VITAMIN E, OXIDATIVE STRESS, AND INFLAMMATION, Annual Review of Nutrition, 10.1146/annurev.nutr.24.012003.132446, 25:1, (151-174), Online publication date: 21-Aug-2005. July 2004Vol 24, Issue 7 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000131259.97572.99PMID: 15237091 Originally publishedJuly 1, 2004 PDF download Advertisement" @default.
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