Advertisement

Mechanisms of Atherosclerosis: Role of LDL Oxidation

  • Peter D. Reaven
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 366)

Abstract

There is now extensive evidence suggesting that atherosclerosis begins with the formation of foam cells (the initial stage of the fatty streak) underneath an intact endothelial layer (1). An early step in foam cell formation is the adherence of monocytes to the endothelium overlying an initial accumulation of cholesterol. Subsequently, the monocytes enter the artery wall through cell gap junctions, presumably attracted by a variety of chemoattractants. Within the subendothelial space, monocytes differentiate into macrophages which may then take up lipoproteins (smooth muscle cells may also take up lipoproteins, although to a lesser extent) forming foam cells. The fatty streak, through a series of poorly defined steps, may develop into complex atherosclerotic lesions, called fibrous plaques, which may eventually lead to clinically apparent coronary artery disease (CAD). The fibrous plaques are covered by a thick cap of connective tissue and smooth muscle cells and overlay a core of necrotic cellular debris and lipid. Plaques may eventually grow large enough that they can project into the lumen of the artery, reducing blood flow. Most clinical events, such as myocardial infarctions, appear to be due to ruptures, in the margins of the fibrous plaques, which are macrophage-enriched, leading to hemorrhage into the plaque with subsequent thromboses and acute occlusion of the vessel.

Keywords

Atherosclerotic Lesion Foam Cell Artery Wall Serum Selenium Foam Cell Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    R. Ross, The pathogenesis of atherosclerosis: a perspective for the 1990s, Nature 362(6423):801–809 (1993).PubMedCrossRefGoogle Scholar
  2. 2.
    D. Steinberg and J.L. Witztum, Lipoproteins and atherogenesis: Current concepts, JAMA 264(23):3047–3052 (1990).PubMedCrossRefGoogle Scholar
  3. 3.
    D. Steinberg, S. Parthasarathy, T.E. Carew, J.C. Khoo, and J.L. Witztum, Beyond cholesterol: Modifications of low density lipoprotein that increase its atherogenicity, New Engl J Med 320:915–924 (1989).PubMedCrossRefGoogle Scholar
  4. 4.
    J.L. Goldstein, Y.K. Ho, S.K. Basu, and M.S. Brown, Binding site on macrophage that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition, Proc Natl Acad Sci USA 76:333–337 (1979).PubMedCrossRefGoogle Scholar
  5. 5.
    M. Freeman, Y. Ekkel, L. Rohrer, M. Penman, N.J. Freedman, G.M. Chisolm, and M. Krieger, Expression of type I and type II bovine scavenger receptors in Chinese hamster ovary cells: lipid droplet accumulation and non-reciprocal cross competition by acetylated and oxidized low density lipoprotein, Proc Natl Acad Sci USA 88(11):4931–4935 (1991).PubMedCrossRefGoogle Scholar
  6. 6.
    W. Palinski, M.E. Rosenfeld, S. Ylä-Herttuala, G.C. Gurtner, S.A. Socher, S.W. Butler, S. Parthasarathy, T.E. Carew, D. Steinberg, and J.L. Witztum, Low density lipoprotein undergoes oxidative modification in vivo, Proc Natl Acad Sci USA 86: 1372–1376 (1989).PubMedCrossRefGoogle Scholar
  7. 7.
    Ylä-Herttuala S, Palinski W, Rosenfeld ME, S. Parthasarathy, T.E. Carew, S. Butler, J.L. Witztum, and D. Steinberg, Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man, J Clin Invest 84(4): 1086–1095 (1989).PubMedCrossRefGoogle Scholar
  8. 8.
    M.E. Rosenfeld, W. Palinski, S. Ylä-Herttuala, S. Butler, and J.L. Witztum, Distribution of oxidation-specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits, Arteriosclerosis 10(3):336–349 (1990).PubMedCrossRefGoogle Scholar
  9. 9.
    M.E. Haberland, D. Fong, and L. Cheng, Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits, Science 241(4862):215–218 (1988).PubMedCrossRefGoogle Scholar
  10. 10.
    H.C. Boyd, A.M. Gown, G. Wolfbauer, and A. Chait, Direct evidence for a protein recognized by a monoclonal antibody against oxidatively modified LDL in atherosclerotic lesions from a Watanabe heritable hyperlipidemic rabbit, Am J of Path 135(5):815–825 (1989).Google Scholar
  11. 11.
    U.P. Steinbrecher, S. Parthasarathy, D.S. Leake, J.L. Witztum, and D. Steinberg, Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids, Proc Natl Acad Sci USA 83:3883–3887 (1984).CrossRefGoogle Scholar
  12. 12.
    S. Parthasarathy, D.J. Printz, D. Boyd, L. Joy, and D. Steinberg, Macrophage oxidation of low density lipoprotein generates a modified form recognized by the scavenger receptor, Arteriosclerosis 6:505–510 (1986).PubMedCrossRefGoogle Scholar
  13. 13.
    J.W. Heinecke, H. Rosen, and A. Chait, Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture, J Clin Invest 74(5): 1890–1894 (1984).PubMedCrossRefGoogle Scholar
  14. 14.
    J.L. Witztum and D. Steinberg, Role of oxidized low density lipoprotein in atherogenesis, J Clin Invest 88:1785–1792 (1991).PubMedCrossRefGoogle Scholar
  15. 15.
    H. Esterbauer, O. Quehenberger, and G. Jürgens, Oxidation of human low density lipoprotein with special attention to aldehydic lipid peroxidation products. in: “Free Radicals: Methodology and Concepts,” C. Rice-Evans and B. Halliwell, eds., The Richelieu Press, London (1988), pp 243–268.Google Scholar
  16. 16.
    S. Parthasarathy, U.P. Steinbrecher, J. Barnett, J.L. Witztum, and D. Steinberg, Essential role of phospholipase A2 activity in endothelial cell-induced modification of low density lipoprotein, Proc Natl Acad Sci USA 82(9):3000–3004 (1985).PubMedCrossRefGoogle Scholar
  17. 17.
    C.P. Sparrow, S. Parthasarathy, and D. Steinberg, A macrophage receptor that recognizes oxidized low density lipoprotein but not acetylated low density lipoprotein, J Biol Chem 264:2599–2604 (1989).PubMedGoogle Scholar
  18. 18.
    H. Arai, T. Kita, M. Yokode, S. Narumiya and C. Kawai, Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: different uptake mechanisms for acetylated and oxidized low density lipoproteins, Biochem Biophys Res Comm 159(3): 1375–1382 (1989).PubMedCrossRefGoogle Scholar
  19. 19.
    Y.B. de Rijke and T.J.C. Van Berkel, Rat liver Kupffer and endothelial cells express different binding proteins for modified low density lipoproteins, J Biol Chem 269:824–827 (1994).PubMedGoogle Scholar
  20. 20.
    D.J. Lamb and D.S. Leake, CD4-positive T-lymphocytes can oxidatively modify low density lipoprotein, Biochem Soc Transactions, 21(2): 1328 (1993).Google Scholar
  21. 21.
    M.E. Rosenfeld, J.C. Khoo, E. Miller, S. Parthasarathy, W. Palinski, and J.L. Witztum, Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of LDL, and contain oxidation specific lipid-protein adducts, J Clin Invest 87:90–99 (1991).PubMedCrossRefGoogle Scholar
  22. 22.
    S. Parthasarathy, Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL receptor, Biochim Biophys Acta. 917(2): 1328 (1987).Google Scholar
  23. 23.
    J.W. Heinecke, H. Rosen, L.A. Suzuki, and A. Chait, The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells, J Biol Chem 262(21): 10098–10103 (1987).PubMedGoogle Scholar
  24. 24.
    K. Hiramatsu, H. Rosen, J.W. Heinecke, G. Wolfbauer, and A. Chait, Superoxide initiates oxidation of low density lipoprotein by human monocytes. Arterioscler 7:55–60 (1987).CrossRefGoogle Scholar
  25. 25.
    C.P. Sparrow, S. Parthasarathy, and D. Steinberg, Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modification, J Lipid Res 29:745–753 (1988).PubMedGoogle Scholar
  26. 26.
    S. Parthasarathy, E. Wieland, and D. Steinberg, A role for endothelial cells lipoxygenase in the oxidative modification of low density lipoprotein, Proc Natl Acad Sci USA 86:1046–1050 (1989).PubMedCrossRefGoogle Scholar
  27. 27.
    S. Ylä-Herttuala, M.E. Rosenfeld, S. Parthasarathy, E. Sigal, T. Sarkioja, J.L. Witztum, and D. Steinberg, Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA co-localize with oxidation specific lipid-protein adducts, J. Clin Invest 87(4): 1146–1152 (1991).PubMedCrossRefGoogle Scholar
  28. 28.
    D.J. Benz, N. Mori-Ito, J.L. Witztum, A. Miyanohara, T. Friedmann, D. Steinberg, and S. Parthasarathy, Expression of 15-lipoxygenase in fibroblasts confers an enhanced capacity to oxidatively modify LDL (Presented Abstract), Circulation 86:1–209 (1992), (Submitted).CrossRefGoogle Scholar
  29. 29.
    L. Hongmei, M.I. Cybulsky, M.A. Gimbrone, Jr., and P. Libby, An atherogenic diet rapidly induces VCAM-1, a cytokin-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium, Arterioscler Thromb 13:197–204 (1993).CrossRefGoogle Scholar
  30. 30.
    N. Kume, M.I. Cybulsky, and M.A. Gimbrone, Jr., Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest 90:1138–1144 (1992).PubMedCrossRefGoogle Scholar
  31. 31.
    J.A. Berliner, M.C. Territo, A. Sevanian, et al, Minimally modified low density lipoprotein stimulates monocyte endothelial interactions, J Clin Invest 85:1260–1266 (1990).PubMedCrossRefGoogle Scholar
  32. 32.
    M.T. Quinn, S. Parthasarathy, and D. Steinberg, Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis, Proc Natl Acad Sci USA 85:2805–2809 (1988).PubMedCrossRefGoogle Scholar
  33. 33.
    M.T. Quinn, S. Parthasarathy, L.G. Fong, and D. Steinberg, Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis, Proc Natl Acad Sci USA 84:2995–2998 (1987).PubMedCrossRefGoogle Scholar
  34. 34.
    M.K. Cathcart, D.W. Morel, and G.M. Chisolm, III, Monocytes and neutrophils oxidized low density lipoproteins making it cytotoxic, J Leukocyte Biol 38:341–350 (1985).PubMedGoogle Scholar
  35. 35.
    D.W. Morel, J.R. Hessler, and G.M. Chisolm, Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J Lipid Res 24:1070–1076 (1983).PubMedGoogle Scholar
  36. 36.
    S.D. Cushing, J.A. Berliner, A.J. Valente, M.C. Territo, M. Navab, F. Parhami, R. Gerrity, C.J. Schwartz, and A.M. Fogelman, Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells, Proc Natl Acad Sci USA 87(13):5134–5138 (1990).PubMedCrossRefGoogle Scholar
  37. 37.
    F. Liao, A. Andalibi, F.C. deBeer, A.M. Fogelman, and A.J. Lusis, Genetic control of inflammatory gene induction and NF-Kappa B-like transcription factor activation in response to an atherogenic diet in mice, J Clin Invest 91(6):2572–2579 (1993).PubMedCrossRefGoogle Scholar
  38. 38.
    T.B. Rajavashisth, A. Andalibi, M.C. Territo, J.A. Berliner, M. Navab, A.M. Fogelman, and A.J. Lusis, Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins, Nature 344(6263):254–257 (1990).PubMedCrossRefGoogle Scholar
  39. 39.
    K. Kugiyama, S.A. Kerns, J.D. Morrisett, R. Roberts, and P.D. Henry, Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low density lipoproteins, Nature 344:160–162 (1990).PubMedCrossRefGoogle Scholar
  40. 40.
    H.F. McMurray, S. Parthasarathy, and D. Steinberg, Oxidatively modified low density lipoprotein is a chemoattractant for human T Lymphocytes, J Clin Invest 92:1004–1008 (1993).PubMedCrossRefGoogle Scholar
  41. 41.
    M. Shaikh, S. Martini, J.R. Quiney, P. Baskerville, A.E. LaVille, N.L. Browse, R. Duffield, P.R. Turner, and B. Lewis, Modified plasma-derived lipoproteins in human atherosclerotic plaques, Atherosclerosis 69:165–172 (1988).PubMedCrossRefGoogle Scholar
  42. 42.
    A. Daugherty, B.S. Zweifel, B.E. Sobel, and G. Schonfeld, Isolation of low density lipoprotein from atherosclerotic vascular tissue of Watanabe heritable hyperlipidemic rabbits, Arteriosclerosis 8:768–777 (1988).PubMedCrossRefGoogle Scholar
  43. 43.
    J.T. Salonen, S. Ylä-Herttuala, R. Yamamoto, S. Butler, H. Korpela, R. Salonen, K. Nyyssonen, W. Palinski, and J.L. Witztum, Autoantibody against oxidized LDL and progression of carotid atherosclerosis. Lancet 339(8798):883–887 (1992).PubMedCrossRefGoogle Scholar
  44. 44.
    S. Ylä-Herttuala, W. Palinski, S.W. Butler, S. Picard, and D. Steinberg, Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized low density lipoprotein, Arterioscler Thromb 14:32–40 (1994).PubMedCrossRefGoogle Scholar
  45. 45.
    T.E. Carew, D.C. Schwenke, and D. Steinberg, Antiatherogenic effect of probucol unrelated to its hypercholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit, Proc Natl Acad Sci USA 84:7725–7729 (1987).PubMedCrossRefGoogle Scholar
  46. 46.
    F.K. Gey, Lipids, lipoproteins and antioxidants in cardiovascular dysfunction, Biochemical Society Transactions 18:1041–1045 (1990).PubMedGoogle Scholar
  47. 47.
    M. Eichholzer, H.B. Stähelin, and K.F. Gey, Inverse correlation between essential antioxidants in plasma and subsequent risk to develop cancer, ischemic heart disease and stroke respectively: 12-year follow-up of the Prospective Basel Study, in: “Free Radicals and Aging,” I. Emerit and B. Chance, eds., Birkhäyser /verlag. Basel (1992), pp 398–410.Google Scholar
  48. 48.
    M.J. Stampfer, C.H. Hennekens, J.E. Manson, G.A. Colditz, B. Rosner, and W.C. Willet, Vitamin E consumption and the risk of coronary disease in women, NEJM 328(20): 1444–1449 (1993).PubMedCrossRefGoogle Scholar
  49. 49.
    E.B. Rimm, M.J. Stampfer, A. Ascherio, E. Giovannucci, G.A. Colditz, B. Rosner, and W.C. Willet, Vitamin E consumption and the risk of coronary heart disease in men, NEJM 328(20): 1450–1456 (1993).PubMedCrossRefGoogle Scholar
  50. 50.
    J.M. Gaziano, J.E. Manson, P.M. Ridker, J.E. Buring, and C.H. Hennekens, Beta carotene therapy for chronic stable angina, Circulation 82:Suppl III:III–201 (1990).Google Scholar
  51. 51.
    D.H. Hornig and U. Moser, The safety of high vitamin C intakes in man, in: “Vitamin C (Ascorbic Acid),” J.N. Counsell and D.H. Hornig, eds., Applied Science Publishers Ltd., London. 1st ed. (1981), pp 225–247.Google Scholar
  52. 52.
    S. Fahn, A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson’s Disease, Ann Neurol 32:S128–S132 (1992).PubMedCrossRefGoogle Scholar
  53. 53.
    P.D. Reaven, S. Parthasarathy, B.J. Grasse, E. Miller, F. Almazan, F.H. Mattson, J.C. Khoo, D. Steinberg, and J.L. Witztum, Feasibility of using an oleate-enriched diet to reduce the susceptibility of low density lipoprotein to oxidative modification in humans, Am J Clin Nutr 54:701–706 (1991).PubMedGoogle Scholar
  54. 54.
    P. Reaven, S. Parthasarathy, B.J. Grasse, E. Miller, D. Steinberg, and J.L. Witztum, Effects of oleate-rich and linoleate-rich diets on the susceptibility of low density lipoprotein to oxidative modification in hypercholesterolemic subjects, J Clin Invest 91:668–676 (1993).PubMedCrossRefGoogle Scholar
  55. 55.
    A. Bonanome, A. Pagnan, S. Biffanti, A. Opportuno, F. Sorgato, M. Dorella, M. Maiorino, and F. Ursini, Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification, Arterioscler. Thromb. 12:529–533 (1992).PubMedCrossRefGoogle Scholar
  56. 56.
    M. Abbey, G.B. Belling, M. Noakes, F. Hirata, and P.J. Nestel, Oxidation of lowdensity lipoproteins: intra-individual variability and the effect of dietary linoleate supplementation, Am. J. Clin. Nutr. 57:391–398 (1993).PubMedGoogle Scholar
  57. 57.
    P.D. Reaven, B.J. Grasse, and D.L. Tribble, Effects of linoleate-rich and oleate-rich diets in combination with α-tocopherol on the susceptibility of low-density lipoproteins (LDL) and LDL subfractions to oxidative modification in humans, Arterioscler. Thromb. 14:557–566 (1994).PubMedCrossRefGoogle Scholar
  58. 58.
    H. Esterbauer, M. Dieber-Rotheneder, G. Striegl, and G. Waeg, Role of vitamin E in preventing the oxidation of low-density lipoprotein, Am. J. Clin. Nutr 53:314S–321S (1991).PubMedGoogle Scholar
  59. 59.
    P.D. Reaven, A. Khouw, W. Beltz, S. Parthasarathy, and J.L. Witztum, Effect of dietary antioxidant combinations in humans: Protection of LDL by vitamin E, but not by ß-carotene, Arterioscler. Thromb. 13:590–600 (1993).PubMedCrossRefGoogle Scholar
  60. 60.
    P.D. Reaven and J.L. Witztum, Comparison of supplementation of RRR-α-tocopherol and racemic-a-tocopherol in humans: Effects on lipid levels and lipoprotein susceptibility to oxidation, Arterioscler. Thromb. 13:601–608 (1993).PubMedCrossRefGoogle Scholar
  61. 61.
    H. Princen, G. van Poppel, C. Vogelezang C, R. Buytenhek, F.J. Kok, Supplementation with vitamin E but not β-carotene in vivo protects low density lipoprotein from lipid peroxidation in vitro: Effect of cigarette smoking, Arterioscler Thromb 12:554–562 (1992).PubMedCrossRefGoogle Scholar
  62. 62.
    I. Jialal and S.M. Grundy, Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein, J Lipid Res 33:899–906 (1992).PubMedGoogle Scholar
  63. 63.
    D. Mohr, V.W. Bowry, and R. Stocker, 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 (1992).PubMedCrossRefGoogle Scholar
  64. 64.
    P. Reaven, E. Ferguson, M. Navab, and F. Powell, Susceptibility of human low density lipoprotein to oxidative modification: Effects of variations in β-carotene concentration and oxygen tension, Arterioscler Thromb In press (1994).Google Scholar
  65. 65.
    S. Parthasarathy, Evidence for an additional intracellular site of action of probuco1 in the prevention of oxidative modification of low density lipoproteins: Use of a new water-soluble probucol derivative, J Clin Invest 89:1618–1621 (1992).PubMedCrossRefGoogle Scholar
  66. 66.
    M. Navab, S.S. Imes, S.Y. Hama, G.P. Hough, L.A. Ross, R.W. Bork, A.J. Valente, J.A. Berliner, D.C. Drinkwater, H. Laks, and A.M. Fogelman, Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein, J Clin Invest 88:2039–2046 (1991).PubMedCrossRefGoogle Scholar
  67. 67.
    T. Kita, Y. Nagano, M. Yokode, K. Ishii, N. Kume, A. Ooshima, H. Yoshica, and C Kawai, Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia, Proc Natl Acad Sci USA 84:5928–5931 (1987).PubMedCrossRefGoogle Scholar
  68. 68.
    A. Daugherty, B.S. Zweifel, and G. Schonfeld, Probucol attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits, Br J Pharmacol 98:612–618 (1989).PubMedCrossRefGoogle Scholar
  69. 69.
    Y. Stein, O. Stein, B. Delplanque, J.D. Fesmire, D.M. Lee, and P. Alaupovic, Lack of effect of probucol on atheroma formation in cholesterol-fed rabbits kept at comparable cholesterol levels, Atherosclerosis 75:145–155 (1989).PubMedCrossRefGoogle Scholar
  70. 70.
    Y. Nagano, T. Nakamura, Y. Matsuzawa, M. Cho, Y. Ueda, and T. Kita, Probucol and atherosclerosis in the Watanabe heritable hyperlipidemic rabbit — long-term antiatherogenic effect and effects on established plaques, Atherosclerosis 92:131–140 (1992).PubMedCrossRefGoogle Scholar
  71. 71.
    S.J.T. Mao, M.T. Yates, R.A. Parker, E.M. Chi, and R.L. Jackson, Attenuation of atherosclerosis in a modified strain of hypercholesterolemic Watanabe rabbits using a probucol analog (MDL 29,311) that does not lower serum cholesterol, Arterioscler Thromb 11:1266–1275 (1991).PubMedCrossRefGoogle Scholar
  72. 72.
    M. Sasahara, E.W. Raines, T.E. Carew, D. Steinberg, P.W. Wahl, A. Chait, and R. Ross, Inhibition of hypercholesterolemia-induced atherosclerosis in Macaca Nemestrina by probucol: I. Intimai lesion area correlates inversely with resistance of lipoproteins oxidation, J Clin Invest In press (1994).Google Scholar
  73. 73.
    C.P. Sparrow, T.W. Doebber, J. Olszewski, M.S. Wu, J. Ventre, K.A. Stevens, and Y.S. Chao, Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N’-diphenyl-phenylenediamine, J Clin Invest 89:1885–1891 (1992).PubMedCrossRefGoogle Scholar
  74. 74.
    I. Björkhem, A. Henriksson-Freyschuss, O. Breuer, U. Diczfalusy, L. Berglund, and P. Henriksson, The antioxidant butylated hydroxytoluene protects against atherosclerosis, Arterioscler Thromb 11:15–22 (1991).PubMedCrossRefGoogle Scholar
  75. 75.
    T.M.A. Bocan, S.B. Mueller, E.Q. Brown, P.D. Uhlendorf, M.J. Mazur, R.S. Newton, Antiatherosclerotic effects of antioxidants are lesion-specific when evaluated in hypercholesterolemic New Zealand White rabbits, Exp Molec Pathol 57:70–83 (1992).CrossRefGoogle Scholar
  76. 76.
    A.J. Verlangieri and M.J. Bush, Effects of d-a-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr 11(2): 131–138 (1992).PubMedGoogle Scholar
  77. 77.
    F.J. Kok, A.M. de Bruijn, R. Vermeeren, A. Hofman, A. van Laar, M. de Bruin, R.J.J. Hermus, and H.A. Valkenburg, Serum selenium, vitamin antioxidants, and cardiovascular mortality: a 9-year follow-up study in the Netherlands, Am J Clin Nutr 45:462–468 (1987).PubMedGoogle Scholar
  78. 78.
    J.T. Salonen, R. Salonen, I. Penttilä, J. Herranen, M. Jauhiainen, M. Rantola, R. Lappeteläinen, P.H. Mäenpää, G. Alfthan, and P. Puska, Serum fatty acids, apolipoproteins, selenium and vitamin antioxidants and the risk of death from coronary artery disease, Am J Cardiol 56:226–231 (1985).PubMedCrossRefGoogle Scholar
  79. 79.
    C. Bolton-Smith, M. Woodward, and H. Tunstall-Pedoe, The Scottish Heart Health Study. Dietary intake by food frequency questionnaire and odds ratios for coronary heart disease risk. II. The antioxidant vitamins and fibre, Europ J Clin Nutr 46:85–93 (1992).Google Scholar
  80. 80.
    A.F.M. Kardinaal, F.J. Kok, J. Ringstad, J. Gomez-Aracena, V.P. Mazaev, L. Kohlmeier, B.C. Martin, A. Aro, J.D. Kark, M. Delgado-Rodriguez, R.A. Riemersma, P. van’t Veer, J.K. Huttunen, and J.M. Martin-Moreno, Antioxidants in adipose tissue and risk of myocardial infarction: the EURAMIC study, Lancet 342:1379–1384 (1993).PubMedCrossRefGoogle Scholar
  81. 81.
    R.A. Riemersma, D.A. Wood, C.C.A. MacIntyre, R.A. Elton, K.F. Gey, and M.F. Oliver, Risk of angina pectoris and plasma concentrations of vitamins A, C and E and carotene, Lancet 337:1–5 (1991).PubMedCrossRefGoogle Scholar
  82. 82.
    J.M. Gaziano, J.E. Manson, L.G. Branch, F. LaMotte, G.A. Colditz, J.E. Buring, and C.H. Hennekens, Dietary beta carotene and decreased cardiovascular mortality in an elderly cohort, Abstract # 982-14, JACC 19(3):377A (1992).Google Scholar
  83. 83.
    J.E. Enstrom, L.E. Kanim, and M.A. Klein, Vitamin C intake and mortality among a sample of the United States population, Epidemiology 3(3): 194–202 (1992).PubMedCrossRefGoogle Scholar
  84. 84.
    J.T. Salonen, R. Salonen, R. Seppänen, M. Rantola, M. Parviainen, G. Alfthan, P.H. Mäenpää, E. Taskinen, and R. Rauramaa, Relationship of serum selenium and antioxidants to plasma lipoproteins, platelet aggregability and prevalent ischaemic heart disease in Eastern Finnish men, Atherosclerosis 70:155–160 (1988).PubMedCrossRefGoogle Scholar
  85. 85.
    J.T. Salonen, R. Salonen, H. Korpela, S. Suntioinen, and J. Tuomilehto, Serum copper and the risk of acute myocardial infarction: A prospective population study in men in Eastern Finland, Am J Epidemiol 134(3):268–276 (1991).PubMedGoogle Scholar
  86. 86.
    J.T. Salonen, K. Nyyssönen, H. Korpela, J. Tuomilehto, R. Seppänen, and R. Salonen, High stored iron levels are associated with excess risk of myocardial infarction in Eastern Finnish men, Circulation 86(3): 803–811 (1992).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Peter D. Reaven
    • 1
  1. 1.Division of Endocrinology and Metabolism Department of MedicineUniversity of CaliforniaSan Diego La JollaUSA

Personalised recommendations