Tocopherol-mediated peroxidation of lipoproteins: Implications for vitamin E as a potential antiatherogenic supplement

FASEB Journal

Volumn 13, Issue 9, 1999, Pages 977-994

  Upston, Joanne M ^a   Terentis, Andrew C ^a   Stocker, Roland ^a  

^a HEART RESEARCH INSTITUTE   (Australia)

Author keywords

Antioxidants; Atherosclerosis; LDL; Lipid peroxidation

Indexed keywords

2 HYDROXYESTRADIOL; 3 HYDROXYANTHRANILIC ACID; ADRENALIN; ALPHA TOCOPHEROL; ALPHA TOCOPHERYLQUINONE; ASCORBIC ACID; BILIRUBIN; BUTYLATED HYDROXYANISOLE; BUTYLCRESOL; CAFFEIC ACID; LIPOPROTEIN; LOW DENSITY LIPOPROTEIN; N,N' DIPHENYL 1,4 PHENYLENEDIAMINE; TERT BUTYLHYDROQUINONE; TROLOX C; UBIQUINONE DERIVATIVE;

ALPHA TOCOPHEROL DEFICIENCY; ARTERY WALL; ATHEROSCLEROSIS; CONTROLLED STUDY; CORONARY ARTERY DISEASE; DIET SUPPLEMENTATION; HUMAN; HUMAN TISSUE; LIPID PEROXIDATION; MAJOR CLINICAL STUDY; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; VITAMIN INTAKE;

EID: 0033006542     PISSN: 08926638     EISSN: None     Source Type: Journal    
DOI: 10.1096/fasebj.13.9.977     Document Type: Review

References (151)

1. Kannel, W. B., Castelli, W. P., and Gordon, T. (1971) Serum cholesterol, lipoproteins, and the risk of coronary heart disease. Ann. Int. Med. 74, 1-12
2. Goldstein, J. L., Basu, S. K., and Brown, M. S. (1983) Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 98, 241-260
3. Goldstein, J. L., Ho, Y. K., Basu, S. K., and Brown, M. S. (1979) 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. 76, 333-337
4. Henriksen, T., Mahoney, E. M., and Steinberg, D. (1981) Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc. Natl. Acad. Sci. U. S. A. 78, 6499-6503
5. Zhang, H., Yang, Y., and Steinbrecher, U. P. (1993) Structural requirements for the binding of modified proteins to the scavenger receptor of macrophages. J. Biol. Chem. 268, 5535-5542
6. Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C., and Witztum, J. L. (1989) Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 320, 915-924
7. Steinbrecher, U. P., Zhang, H., and Lougheed, M. (1990) Role of oxidatively modified LDL in atherosclerosis. Free Rad. Biol. Med. 9, 155-168
8. Ylä-Herttuala, S., Palinski, W., Rosenfeld, M. E., Parthasarathy, S., Carew, T. E., Butler, S., Witztum, J. L., and Steinberg, D. (1989) Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J. Clin. Invest. 84, 1086-1095
9. Ross, R. (1993) The pathogenesis of atheroslcerosis: a perspective for the 1990s. Nature (London) 362, 801-809
10. Berliner, J. A., and Heinecke, J. W. (1996) The role of oxidized lipoproteins in atherogenesis. Free Rad. Biol. Med. 20, 707-727
11. Diaz, M. N., Frei, B., Vita, J. A., and Kearney, J. F., Jr. (1997) Antioxidants and atherosclerotic heart disease. N. Engl. J. Med. 337, 408-416
12. Smith, E. B., Evans, P. H., and Downham, M. D. (1967) Lipid in the aortic intima. The correlation of morphological and chemical characteristics. J. Atheroscler. Res. 7, 171-186
13. Itabe, H., Takeshima, E., Iwasaki, H., Kimura, J., Yoshida, Y., T. Imanaka, and Takano, T. (1994) A monoclonal antibody against oxidized lipoprotein recognizes foam cells in atherosclerotic lesions. Complex formation of oxidized phosphatidylcholines and polypeptides. J. Biol. Chem. 269, 15274-15279
14. Hazell, L. J., Arnold, L., Flowers, D., Waeg, G., Malle, E., and Stocker, R. (1996) Presence of hypochlorite-modified proteins in human atherosclerotic lesions. J. Clin. Invest. 97, 1535-1544
15. Hoff, H. F., and Hoppe, G. (1995) Structure of cholesterol-containing particles accumulating in atherosclerotic lesions and the mechanisms of their derivation. Curr. Opin. Lipidol. 6, 317-325
16. Burton, G. W., and Ingold, K. U. (1986) Vitamin E: application of the principles of physical organic chemistry to the exploration of its structure and function. Acc. Chem. Res. 19, 194-201
17. Esterbauer, H., Gebicki, J., Puhl, H., and Jürgens, G. (1992) The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Rad. Biol. Med. 13, 341-390
18. Bowry, V. W., Ingold, K. U., and Stocker, R. (1992) Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant. Biochem. J. 288, 341-344
19. Bowry, V. W., and Stocker, R. (1993) Tocopherol-mediated peroxidation. The pro-oxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J. Am. Chem. Soc. 115, 6029-6044
20. Kontush, A., Finckh, B., Karten, G., Kohlschütter, A., and Beisiegel, U. (1996) Antioxidant and prooxidant activity of α-tocopherol in human plasma and low density lipoprotein. J. Lipid Res. 37, 1436-1448
21. Iwatsuki, M., Niki, E., Stone, D., and Darley-Usmar, V. M. (1995) α-Tocopherol mediated peroxidation in the copper (II) and met myoglobin induced oxidation of human low density lipoprotein: the influence of lipid hydroperoxides. FEBS Lett. 360, 271-276
22. Neuzil, J., Thomas, S. R., and Stocker, R. (1997) Requirement for, promotion, or inhibition by α-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation. Free Rad. Biol. Med. 22, 57-71
23. Kontush, A., Meyer, S., Finckh, B., Kohlschütter, A., and Beisiegel, U. (1996) α-Tocopherol as a reductant for Cu(II) in human lipoproteins. Triggering role in the initiation of lipoprotein oxidation. J. Biol. Chem. 271, 11106-11112
24. Stocker, R. (1994) Lipoprotein oxidation: mechanistic aspects, methodological approaches and clinical relevance. Curr. Opin. Lipidol. 5, 422-433
25. Esterbauer, H., Striegl, G., Puhl, H., and M. Rotheneder. (1989) Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Rad. Res. Commun. 6, 67-75
26. Jürgens, G., Hoff, H. F., Chisolm, G. M., and Esterbauer, H. (1987) Modification of human low density lipoprotein by oxidation - characterization and pathophysiological implications. Chem. Phys. Lipids, 45, 315-336
27. Jialal, I., and Grundy, S. M., (1992) Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J. Lipid Res. 33, 899-906
28. Kleinveld, H. A., Demacker, P. N., and Stalenhoef, A. F. (1994) Comparative studies on the effect of low-dose vitamin E and probucol on the susceptibility of LDL to oxidation and the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Arterioscler. Thromb. 14, 1386-1391
29. Ingold, K. U., Bowry, V. W., Stocker, R., and Walling, C. (1993) Autoxidation of lipids and antioxidation by α-tocopherol and ubiquinol in homogeneous solution and in aqueous dispersions of lipids. The unrecognized consequences of lipid particle size as exemplified by the oxidation of human low density lipoprotein. Proc. Natl. Acad. Sci. U. S. A. 90, 45-49
30. Witting, P. K., Bowry, V. W., and Stocker, R. (1995) Inverse deuterium kinetic isotope effect for peroxidation in human low-density lipoprotein (LDL): a simple test for tocopherol-mediated peroxidation of LDL lipids. FEBS Lett. 375, 45-49
31. Witting, P. K., Upston, J. M., and Stocker, R. (1997) The role of α-tocopheroxyl radical in the initiation of lipid peroxidation in human low density lipoprotein exposed to horseradish peroxidase. Biochemistry 36, 1251-1258
32. Dieber-Rotheneder, M., Puhl, H., Waeg, G., Striegl, G., and Esterbauer, H. (1991) Effect of oral supplementation with D-alpha-tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation. J. Lipid Res. 32, 1325-1332
33. Witting, P. K., Upston, J. M., and Stocker, R. (1998) in Subcellular Biochemistry: Fat-Soluble Vitamins (Quinn, P., and Kagan, V., eds) pp 345-390, Plenum, London
34. Niki, E., Kawakami, A., Saito, M., Yamamoto, Y., Tsuchiya, J., and Kamiya, Y. (1985) Effect of phytyl side chain of vitamin E on its antioxidant activity. J. Biol. Chem. 260, 2191-2196
35. Waldeck, A. R., and Stocker, R. (1996) Radical-initiated lipid peroxidation in low density lipoproteins: Insights obtained from kinetic modeling. Chem. Res. Toxicol. 9, 954-964
36. Halliwell, B., and Gutteridge, J. M. C. (1989) Free radicals in biology and medicine, 2nd ed., Clarendon, Oxford
37. Bowry, V. W., Stanley, K. K., and Stocker, R. (1992) High density lipoprotein is the major carrier of lipid hydroperoxides in fasted human plasma. Proc. Natl. Acad. Sci. U. S. A. 89, 10316-10320
38. Mohr, D., and Stocker, R. (1994) Radical-mediated oxidation of isolated human very low density lipoprotein. Arterioscl. Thromb. 14, 1186-1192
39. Upston, J. M., Neuzil, J., Witting, P. K., Alleva, R., and Stocker, R. (1997) 15-Lipoxygenase-induced enzymic oxidation of low density lipoprotein associated free fatty acids stimulates non-enzymic, α-tocopherol-mediated peroxidation of cholesteryl esters. J. Biol. Chem. 272, 30067-30074
40. Ingold, K. U., and Howard, J. A. (1962) Reaction of phenols with peroxy radicals. Nature (London) 195, 280-281
41. Burton, G. W., and Ingold, K. U. (1981) Autoxidation of biological molecules. 1. The antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro. J. Am. Chem. Soc. 103, 6472-6477
42. Traber, M. G., Sokol, R. J., Burton, G. W., Ingold, K. U., Papas, A. M., Huffaker, J. E., and Kayden, H. J. (1990) Impaired ability of patients with familial isolated vitamin E deficiency to incorporate α-tocopherol. J. Clin. Invest. 85, 397-407
43. Ziouzenkova, O., Sevanian, A., Abuja, P. M., Ramos, P., and Esterbauer, H. (1998) Copper can promote oxidation of LDL by markedly different mechanisms. Free Rad. Biol. Med. 24, 607-623
44. Lynch, S. M., and Frei, B. (1995) Reduction of copper, but not iron, by human low density lipoprotein (LDL). Implications for metal ion-dependent oxidative modification of LDL. J. Biol. Chem. 270, 5158-5163
45. Hazell, L. J., van den Berg, J. J. M., and Stocker, R. (1994) Oxidation of low-density lipoprotein by hypochlorite causes aggregation that is mediated by modification of lysine residues rather than lipid oxidation. Biochem. J. 302, 297-304
46. Hazell, L. J., and Stocker, R. (1997) α-Tocopherol does not inhibit hypochlorite-induced oxidation of apolipoprotein B-100 of low-density lipoprotein. FEBS Lett. 414, 541-544
47. Nagaoka, S., Okauchi, Y., Urano, S., Nagashima, U., and Mukai, K. (1990) Kinetic and ab initio study of the prooxidant effect of vitamin E. Hydrogen abstraction from fatty acid esters and egg yolk lecithin. J. Am. Chem. Soc. 112, 8921-8924
48. Doba, T., Burton, G. W., and Ingold, K. U. (1985) Antioxidant and co-antioxidant activity of vitamin C. The effect of vitamin C, either alone or in the presence of vitamin E or a water-soluble vitamin E analogue, upon the peroxidation of aqueous multilamellar phospholipid liposomes. Biochim. Biophys. Acta 835, 298-303
49. Bowry, V. W., Mohr, D., Cleary, J., and Stocker, R. (1995) Prevention of tocopherol-mediated peroxidation of ubiquinol-10-free human low density lipoprotein. J. Biol. Chem. 270, 5756-5763
50. Phair, R. D., Hammond, M. G., Bowden, J. A., Fried, M., Fisher, W. R., and Berman, M. (1975) A preliminary model for human lipoprotein metabolism in hyperlipoproteinemia. Federation Proc. 34, 2263-2270
51. Neuzil, J., Witting, P. K., and Stocker, R. (1997) α-Tocopheryl hydroquinone is an efficient multifunctional inhibitor of radical-initiated oxidation of low-density lipoprotein lipids. Proc. Natl. Acad. Sci. U. S. A. 94, 7885-7890
52. Neuzil, J., and Stocker, R. (1994) Free and albumin-bound bilirubin is an efficient co-antioxidant for α-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J. Biol. Chem. 269, 16712-16719
53. Witting, P. K., Westerlund, C., and Stocker, R. (1996) A rapid and simple screening test for potential inhibitors of tocopherol-mediated peroxidation of LDL lipids. J. Lipid Res. 37, 853-867
54. Thomas, S. R., Witting, P. K., and Stocker, R. (1996) 3-Hydroxyanthranilic acid is an efficient, cell-derived co-antioxidant for α-tocopherol, inhibiting human low density lipoprotein and plasma lipid peroxidation. J. Biol Chem. 271, 32714-32721
55. Stocker, R., and Frei, B. (1991) in Oxidative stress: Oxidants and antioxidants (Sies, H., Ed.) pp 213-243, Academic Press, London.
56. Sattler, W., Mohr, D., and Stocker, R. (1994) Rapid isolation of lipoproteins and assessment of their peroxidation by HPLC postcolumn chemiluminescence. Methods Enzymol. 233, 469-489
57. Jessup, W., Mohr, D., Gieseg, S. P., Dean, R. T., and Stocker, R. (1992) The participation of nitric oxide in cell free-and its restriction of macrophage-mediated oxidation of low-density lipoprotein. Biochim. Biophys. Acta 1180, 73-82
58. Hazell, L. J., and Stocker, R. (1993) Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages. Biochem. J. 290, 165-172
59. Wagner, J. R., Motchnik, P. A., Stocker, R., Sies, H., and Ames, B. N. (1993) The oxidation of blood plasma and low density lipoprotein components by chemically generated singlet oxygen. J. Biol. Chem. 268, 18502-18506
60. Frei, B., Kim, M., and Ames, B. N. (1990) Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc. Natl. Acad. Sci. U. S. A. 87, 4879-4883
61. Mohr, D., Bowry, V. W., and Stocker, R. (1992) Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low density lipoprotein to the initiation of lipid peroxidation. Biochim. Biophys. Acta 1126, 247-254
62. Kontush, A., Hübner, C., Finckh, B., Kohlschütter, A., and Beisiegel, U. (1994) Low density lipoprotein oxidizability by copper correlates to its initial ubiquinol-10 and polyunsaturated fatty acid content. FEBS Lett. 341, 69-73
63. Thomas, S. R., Neuzil, J., and Stocker, R. (1996) Co-supplementation with coenzyme Q prevents the pro-oxidant effect of α-tocopherol and increases the resistance of low-density lipoprotein towards transition metal-dependent oxidation initiation. Arterioscl. Thromb. Vasc. Biol. 16, 687-696
64. Sato, K., Niki, E., and H. Shimasaki. (1990) Free radical-mediated chain oxidation of low density lipoprotein and its synergistic inhibition by vitamin E and vitamin C. Arch. Biochem. Biophys. 279, 402-405
65. Stocker, R., Bowry, V. W., and Frei, B. (1991) Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does α-tocopherol. Proc. Natl. Acad. Sci. U. S. A. 88, 1646-1650
66. Stocker, R., and Suarna, C. (1993) Extracellular reduction of ubiquinone-1 and -10 by human Hep G2 and blood cells. Biochim. Biophys. Acta 1158, 15-22
67. Takahashi, T., Yamaguchi, T., M. Shitashige, Okamoto, T., and Kishi, T. (1995) Reduction of ubiquinone in membrane lipids by rat liver cytosol and its involvement in the cellular defence system against lipid peroxidation. Biochem. J. 309, 883-890
68. Beyer, R. E., Segura-Aguilar, J., Di Bernardo, S., Cavazzoni, M., Fato, R., Fiorentini, D., Galli, M. C., Setti, M., Landi, L., and Lenaz, G. (1996) The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Proc. Natl. Acad. Sci. U. S. A. 93, 2528-2532
69. Frei, B., Stocker, R., and Ames, B. N. (1988) Antioxidant defenses and lipid peroxidation in human blood plasma. Proc. Natl. Acad. Sci. U. S. A. 85, 9748-9752
70. Frei, B., England, L., and Ames, B. N. (1989) Ascorbate is an outstanding antioxidant in human blood plasma. Proc. Natl. Acad. Sci. U. S. A. 86, 6377-6381
71. Barclay, L. R. C., Locke, S. J., and MacNeil, J. M. (1985) Autoxidation in micelles. Synergism of vitamin C with lipid-soluble vitamin E and water-soluble Trolox. Can. J. Chem. 63, 366-374
72. Packer, J. E., Slater, T. F., and Willson, R. L. (1979) Direct observation of a free radical interaction between vitamin E and vitamin C. Nature (London) 278, 737-738
73. Kagan, V. E., Serbinova, E. A., Forte, T., Scita, G., and Packer, L. (1992) Recycling of vitamin E in human low density lipoproteins. J. Lipid Res. 33, 385-397
74. Sharma, M. K., and Buettner, G. R. (1993) Interaction of vitamin C and vitamin E during free radical stress in plasma: an ESR study. Free Rad. Biol. Med. 14, 649-653
75. Camejo, G., Rosengren, B., Olson, U., Lopez, F., Olofson, S. O., Westerlund, C., and Bondjers, G. (1990) Molecular basis of the association of arterial proteoglycans with low density lipoproteins: its effect on the structure of the lipoprotein particle. Eur. Heart J. (Suppl. E) 11, 164-173
76. Camejo, G., Hurt-Camejo, E., Rosengren, B., Wiklund, O., Lopez, F., and Bondjers, G. (1991) Modification of copper-catalyzed oxidation of low density lipoprotein by proteoglycans and glycosaminoglycans. J. Lipid Res. 32, 1983-1991
77. Hurt-Camejo, E., Camejo, G., Rosengren, B., Lopez, F., Ahlstrom, C., Fager, G., and Bondjers, G. (1992) Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arterioscler. Thromb. 12, 569-583
78. Salonen, J. T., Ylä-Herttuala, S., Yamamoto, R., Butler, S., Korpela, H., Salonen, R., Nyyssönen, K., Palinski, W., and Witztum, J. L. (1992) Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 339, 883-887
79. Craig, W. Y., Poulin, S. E., Neveux, L. M., Palomaki, G. E., Dostal-Johnson, D. A., Ledue, T. B., and Ritchie, R. F. (1995) Anti-oxidized LDL antibodies and antiphospholipid antibodies in healthy subjects: relationship with lipoprotein-and oxidation-related analytes. J. Autoimmun. 8, 713-726
80. Iribarren, C., Folsom, A. R., Jacobs, D. R., Jr., Gross, M. D., Belcher, J. D., and Eckfeldt, J. H. (1997) Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 17, 1171-1177
81. Van Berkel, T. J., De Rijke, Y. B., and Kruijt, J. K. (1991) Different fate in vivo of oxidatively modified low density lipoprotein and acetylated low density lipoprotein in rats. Recognition by various scavenger receptors on Kupffer and endothelial liver cells. J. Biol. Chem. 266, 2282-2289
82. Cleary, J., Mohr, D., Adams, M. R., Celermajer, D. S., and Stocker, R. (1997) Plasma and LDL levels of major lipophilic antioxidants are similar in patients with advanced atherosclerosis and healthy controls. Free Rad. Res. 26, 175-182
83. Lagendijk, J., Ubbink, J. B., Delport, R., Vermaak, W. J., and Human, J. A. (1997) Ubiquinol/ubiquinone ratio as marker of oxidative stress in coronary artery disease. Res. Commun. Mol. Pathol. Pharmacol. 95, 11-20
84. Ylä-Herttuala, S., Rosenfeld, M. E., Parthasarathy, S., Glass, C. K., Sigal, E., Witztum, J. L., and Steinberg, D. (1990) Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions. Proc. Natl. Acad. Sci. U. S. A. 87, 6959-6963
85. Kuhn, H., Belkner, J., Zaiss, S., Fahrenklemper, T., and Wohlfeil, S. (1994) Involvement of 15-lipoxygenase in early stages of atherogenesis. J. Exp. Med. 179, 1903-1911
86. Daugherty, A., Dunn, J. L. Rateri, D. L., and Heinecke, J. W. (1994) Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J. Clin. Invest. 94, 437-444
87. Hazen, S. L., and Heinecke, J. W. (1997) 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J. Clin. Invest. 99, 2075-2081
88. Fu, S., Davies, M. J., Stocker, R., and Dean, R. T. (1998) Evidence for roles of radicals in protein oxidation in advanced human atherosclerotic plaque. Biochem. J. 333, 519-525
89. Leeuwenburgh, C., Hardy, M. M., Hazen, S. L., Wagner, P., Oh-ishi, S., Steinbrecher, U. P., and Heinecke, J. W. (1997) Reactive nitrogen intermediates promote low density lipoprotein oxidation in human atherosclerotic intima. J. Biol. Chem. 272, 1433-1436
90. Pepin, J. M., O'Neil, J. A., and H. F. Hoff. (1991) Quantification of apo[a] and apoB in human atherosclerotic lesions. J. Lipid Res. 32, 317-327
91. Dabbagh, A. J., and Frei, B. (1995) Human suction blister interstitial fluid prevents metal ion-dependent oxidation of low density lipoprotein by macrophages and in cell-free systems. J. Clin. Invest. 96, 1958-1966
92. Bedwell, S., Dean, R. T., and W. Jessup. (1989) The action of defined oxygen-centered free radicals on human low-density lipoproteins. Biochem. J. 262, 707-712
93. Suarna, C., Dean, R. T., May, J., and Stocker, R. (1995) Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of α-tocopherol and ascorbate. Arterioscler. Thromb. Vasc. Biol. 15, 1616-1624
94. Carpenter, K. L., Cheeseman, K. H., van der Veen, C., Taylor, S. E., Walker, M. K., and Mitchinson, M. J. (1995) Depletion of alpha-tocopherol in human atherosclerotic lesions. Free Rad. Res. 23, 549-558
95. Barclay, L. R., Cameron, R. C., Forrest, B. J. Locke, S. J., Nigam, R., and Vinqvist, M. R. (1990) Cholesterol: free radical peroxidation and transfer into phospholipid membranes. Biochim. Biophys. Acta 1047, 255-263
96. Barclay, L. R. C., Baskin, K. A., Kong, S., and Locke, S. J. (1987) Autoxidation of model membranes. The kinetics and mechanism of autoxidation of mixed phospholipid bilayers. Can. J. Chem. 65, 2541-2550
97. Suarna, C., Dean, R. T., Southwell-Keely, P., Moore, D. E., and Stocker, R. (1997) Separation and characterization of cholesteryl oxo-and hydroxy-linoleate in human atherosclerotic plaque. Free Rad. Res. 27, 397-408
98. Carpenter, K. L., Taylor, S. E., van der Veen, C., Williamson, B. K., Ballantine, J. A., and Mitchinson, M. J. (1995) Lipids and oxidised lipids in human atherosclerotic lesions at different stages of development. Biochim. Biophys. Acta 1256, 141-150
99. Liebler, D. C., Baker, P. F., and Kaysen, K. L. (1990) Oxidation of vitamin E: Evidence for competing autoxidation and peroxyl radical trapping reactions of the tocopheroxyl radical. J. Am. Chem. Soc. 112, 6995-7000
100. Hogg, N., Joseph, J., and B. Kalyanaraman. (1994) The oxidation of α-tocopherol and trolox by peroxynitrite. Arch. Biochem. Biophys. 314, 153-158
101. Liebler, D. C., and Burr, J. A. (1992) Oxidation of vitamin E during iron-catalyzed lipid peroxidation: evidence for electron-transfer reactions of the tocopheroxyl radical. Biochemistry 31, 8278-8284
102. Liebler, D. C. (1993) The role of metabolism in the antioxidant function of vitamin E. Crit. Rev. Toxicol. 23, 147-169
103. Porter, N. A., Weber, B. A., Weenen, H., and Khan, J. A. (1980) Autoxidation of polyunsaturated lipids. Factors controlling the stereochemistry of product hydroperoxides. J. Am. Chem. Soc. 102, 5597-5601
104. Porter, N. A., Lehman, L S., Weber, B. A., and Smith, K. J. (1981) Unified mechanism for polyunsaturated fatty acid autoxidation. Competition of peroxy radical hydrogen atom abstraction, β-scission, and cyclization. J. Am. Chem. Soc. 103, 6447-6455
105. Kenar, J. A., C. M. Havrilla, N. A. Porter, Guyton, J. R., Brown, S. A., Klemp, K. F., and Selinger, E. (1996) Identification and quantification of the regioisomeric cholesteryl linoleate hydroperoxides in oxidized human low density lipoprotein and high density lipoprotein. Chem. Res. Toxicol. 9, 737-744
106. Upston, J. M., Neuzil, J., and Stocker, R. (1996) Oxidation of LDL by recombinant human 15-lipoxygenase: evidence for α-tocopherol dependent oxidation of esterified core and surface lipids. J. Lipid Res. 37, 2650-2661
107. Brooks, C. J. W., Harland, W. A., Steel, G., and Gilbert, J. D. (1970) Lipids of human atheroma: Isolation of hydroxyocta-decadienoic acids from advanced aortal lesions. Biochim. Biophys. Acta 202, 563-566
108. Killion, S. L., Hunter, G. C., Eskelson, C. D., Dubick, M. A., Putnam, C. W., Hall, K. A., Luedke, C. A., Misiorowski, R. L., Schilling, J. D., and McIntyre, K. E. (1996) Vitamin E levels in human atherosclerotic plaque: the influence of risk factors. Atherosclerosis 126, 289-297
109. Gey, K. F., Puska, P., Jordan, P., and Moser, U. K. (1991) Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am. J. Clin. Nutr. 53, 326S-334S
110. Rimm, E. B., Stampfer, M. J., Ascherio, A., Giovannucci, E., Colditz, G. A., and Willett, W. C. (1993) Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 328, 1450-1456
111. Stampfer, M. J., Hennekens, C. H., Manson, J. E., Colditz, G. A., Rosner, B., and Willett, W. C. (1993) Vitamin E consumption and the risk of coronary disease in women. N. Engl. J. Med. 328, 1444-1449
112. Kushi, L. H., Folsom, A. R., Prineas, R. J., Mink, P. J., Wu, Y., and Bostick, R. M. (1996) Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N. Engl. J. Med. 334, 1156-1162
113. Gillilan, R. E., Mondell, B., and Warbasse, J. R. (1977) Quantitative evaluation of vitamin E in the treatment of angina pectoris. Am. Heart J. 93, 444-449
114. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330, 1029-1035
115. Stephens, N. G., Parsons, A., Schofield, P. M., Kelly, F., Cheeseman, K., Mitchinson, M. J., and Brown, M. J. (1996) Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347, 781-786
116. Parker, R. A., Sabrah, T., Cap, M., and Gill, B. T. (1995) Relation of vascular oxidative stress, α-tocopherol, and hypercholesterolemia to early atherosclerosis in hamsters. Arterioscler. Thromb. Vasc. Biol. 15, 349-358
117. Freedman, J. E., Farhat, J. H., Loscalzo, J., and Kearney, J. F., Jr. (1996) α-Tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism. Circulation, 94, 2434-2440
118. Keaney, J. F., Jr., Gaziano, J. M., Xu, A., Frei, B., Curran-Celentano, J., Shwaery, G. T., Loscalzo, J., and Vita, J. A. (1993) Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits. Proc. Natl. Acad. Sci. U. S. A. 90, 11880-11884
119. Pratico, D., Tangirala, R. K., Radar, D., Rokach, J., and FitzGeraldm G. A. (1998) Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in apoE-deficient mice. Nature Med. 4, 1189-1192
120. Thomas, S. R., Neuzil, J., Mohr, D., and Stocker, R. (1995) Co-antioxidants make α-tocopherol an efficient antioxidant for LDL. Am. J. Clin. Nutr. 62, 1357S-1364S
121. Witting, P. K., Pettersson, K., Östlund-Lindqvist, A.-M., Westerlund, C., Westin Eriksson, A., and Stocker, R. (1999) Inhibition by a co-antioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice. FASEB J. 13, 667-675
122. Niu, X., Zammit, V., Upston, J. M., Dean, R. T., and Stocker, R. (1999) Co-existence of oxidized lipids and α-tocopherol in all lipoprotein fractions isolated from advanced human atherosclerotic plaques. Arterioscl. Thromb. Vasc. Biol.
123. Prasad, K., and Kalra, J. (1993) Oxygen free radicals and hypercholesterolemic atherosclerosis: effect of vitamin E. Am. Heart J. 125, 958-973
124. Qiao, Y., Yokoyama, M., Kameyama, K., and Asano, G. (1993) Effect of vitamin E on vascular integrity in cholesterol-fed guinea pigs. Arterioscl. Thromb. 13, 1885-1892
125. Sun, J., Giraud, D. W., Moxley, R. A., and Driskell, J. A. (1997) β-Carotene and α-tocopherol inhibit the development of atherosclerotic lesions in hypercholesterolemic rabbits. Int. J. Vitam. Nutr. Res. 67, 155-163
126. Böger, R. H., Bode-Böger, S. M., Phivthong-ngam, L., Brandes, R. P., Schwedhelm, E., Mügge, A., Böhme, M., Tsikas, D., and Frölich, J. C. (1998) Dietary L-arginine and α-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms. Atherosclerosis 141, 31-43
127. Weitzel, G., Schön, H., Gey, F., and Buddecke, E. (1956) Fettlösliche Vitamine and Atherosklerose. Z. Physiol. Chem. 304
128. Wilson, R. B., Middleton, C. C., and Sun, G. Y. (1978) Vitamin E, andoxidants and lipid peroxidation in experimental atherosclerosis of rabbits. J. Nutr. 108, 1858-1867
129. Westrope, K. L., Miller, R. A., and Wilson, R. B. (1982) Vitamin E in a rabbit model of endogenous hypercholesterolemia and atherosclerosis. Nutr. Rep. Int. 25, 83-88
130. Williams, R. J., Motteram, J. M., Sharp, C. H., and Gallagher, P. J. (1992) Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis 94, 153-159
131. Dam, H. (1944) Ineffectiveness of vitamin E in preventing cholesterol deposition in the aorta. J. Nutr. 28, 289-295
132. Stamler, J., Pick, R., and Katz, L. N. (1954) Failure of vitamin E, vitamin B12 and pancreatic extracts to influence plasma lipids and atherogenesis in cholesterol-fed chicks. Circulation, 8, 455-456
133. Weitzel, G., Schön, H., and Gey, F. (1955) Anti-Atherosklerotische Wirkung Fettlöslicher Vitamine. Klin. Wochenschr. 33, 772-773
134. Beeler, D. A., Rogler, J. C., and Quackenbush, F. W. (1962) Effects of levels of certain dietary lipids on plasma cholesterol and atherosclerosis in the chick. J. Nutr. 78, 184-188
135. Donaldson, W. E. (1982) Atherosclerosis in cholesterol-fed Japanese quail: evidence for amelioration by dietary vitamin E. Poultry Science, 61, 2097-2102
136. Godfried, S. L., Combs, G. F., Saroka, J. M., and Dillingham, L. A. (1989) Potentiation of atherosclerotic lesions in rabbits by high dietary level of vitamin E. Br. J. Nutr. 61, 607-617
137. Smith, T. L., and Kummerow, F. A. (1989) Effect of dietary vitamin E on plasma lipids and atherogenesis in restricted ovulator chickens. Atherosclerosis 75, 105-109
138. W-jcicki, J., Rózewicka, Barcew-Wiszniewska, B., Samochowiec, L., Juzwiak, S., Kadlubowska, D., Tustanowski, S., and Juzyszyn, Z. (1991) Effect of selenium and vitamin E on the development of experimental atherosclerosis in rabbits. Atherosclerosis 87, 9-16
139. Verlangieri, A. J., and Bush, M. J. (1992) Effects of d-α-tocopherol supplementation on experimentally induced primate atherosclerosis. J. Am. Coll. Nutr. 11, 131-138
140. Willingham, A. K., Bolanos, C., Bohannan, E., and Cenedella, R. J. (1993) The effects of high levels of vitamin E on the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. J. Nutr. Biochem. 4, 651-654
141. Keaney, J. F., Jr., Gaziano, J. M., Xu, A., Frei, B., Curran-Celentano, J., Shwaery, G. ., Loscalzo, J., and Vita, J. A. (1994) Low-dose α-tocopherol improves and high-dose α-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits. J. Clin. Invest. 93, 844-851
142. Fruebis, J., Carew, T. E., and Palinski, W. (1995) Effect of vitamin E on atherogenesis in LDL receptor-deficient rabbits. Atherosclerosis 117, 217-224
143. Kleinveld, H. A., Hak-Lemmers, H. L., Hectors, M. P., de Fouw, N. J., Demacker, P. N., and Stalenhoef, A. F. (1995) Vitamin E and fatty acid intervention does not attenuate the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Arterioscler. Thromb. Vasc. Biol. 15, 290-297
144. Munday, J. S., Thompson, K. G., James, K. A., and Manktelow, B. W. (1998) Dietary antioxidants do not reduce fatty streak formation in the C57BL/6 mouse atherosclerosis model. Arterioscler. Thromb. Vasc. Biol. 18, 114-119
145. Schwenke, D. C., and Behr, S. R. (1998) Vitamin E combined with selenium inhibits atherosclerosis in hypercholesterolemic rabbits independently of effects on plasma cholesterol concentrations. Circ. Res. 83, 366-377
146. Bruger, M. (1945) Experimental atherosclerosis. VII. Effect of vitamin E. Proc. Soc. Exp. Biol. Med. 59, 56-57
147. Moses, C., Rhodes, G. L., and Levinson, J. P. (1952) The effect of alpha-tocopherol on experimental aptherosclerosis. Angiology 3, 397-407
148. Xu, R., Yokoyama, W. H., Irving, D., Rein, D., Walzern, R. L., and German, J. B. (1998) Effect of dietary catechin and vitamin E on aortic fatty streak accumulation in hypercholesterolemic hamsters. Atherosclerosis 137, 29-36
149. Özer, N. K., Sirikci, Ö., Taha, S., San, T., Moser, U., and Azzi, A. (1998) Effect of vitamin E and probucol on dietary cholesterol-induced atherosclerosis in rabbits. Free Rad. Biol. Med. 24, 226-233
150. Sulkin, N. M., and Sulkin, D. F. (1960) Intimal lesions in arteries of vitamin E deficient rats. Proc. Soc. Exp. Biol. Med. 103, 111-115
151. Stein, O., Dabach, Y., Hollander, G., Halperin, G., Thiery, J., and Stein, Y. (1996) Relative resistance of the hamster to aortic atherosclerosis in spite of prolonged vitamin E deficiency and dietary hypercholesterolemia. Putative effect of increased HDL? Biochim. Biophys. Acta 1299, 216-222