Inhibition of LDL oxidation by antioxidants

  • Hermann Esterbauer
  • Georg Waeg
  • Herbert Puhl
  • M. Dieber-Rotheneder
  • Franz Tatzber
Part of the EXS book series (EXS, volume 62)


Low density lipoprotein (LDL) consists of about 3000 fatty acids (50% polyunsaturated) and a single molecule apolipoprotein B (500 kDa). The endogenous antioxidants of LDL consist mainly of tocopherols and few carotenoids, which protect the PUFAS against oxidation. That native LDL contains traces of oxidation products has not been proved yet.

Oxidatively modified LDL (oLDL) exhibits cytotoxic and chemotactic activities, furthermore it leads to foam cell formation, a critical step in atherogenesis. The oxidation of LDL is a free radical process and leads to various aldehydic products. The oxidation of LDL is initiated by cells as well as by transition metals like Cu2+. In both cases the oxidation goes through three consecutive phases. The lag-phase is characterized by minimal degradation of PUFAs but a loss of the antioxidants. Thereafter the PUFAs are oxidized to lipid hydroperoxides, which are only intermediates (propagation-phase). These intermediates will decompose to aldehydic products, accompanied by several additional changes in the LDL particle (decomposition-phase). For increased macrophage uptake oLDL must reach the late decomposition-phase; the presence of lipid hydroperoxides in LDL is not sufficient. It is suggested that binding of aldehydes to free amino groups of Apo B is the reason for macrophage uptake. This is supported by the finding that antibodies against aldehyde-modified LDL are able to recognize oxidized LDL in atherosclerotic lesions. Antioxidants like α-tocopherol are able to protect LDL against oxidation. The duration of the lag-phase shows a linear relationship with the content of α-tocopherol in LDL. Yet the efficiency of α-tocopherol to protect LDL shows strong individual variation.


Oxidation Resistance Lipid Hydroperoxide Foam Cell Formation Macrophage Uptake Linoleic Acid Hydroperoxide 
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.


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  1. Avogaro, P., Bittolo-Bon, G., and Cazzolato, G. (1988) Presence of a modified low density lipoprotein in humans. Arteriosclerosis 8: 79–87.PubMedCrossRefGoogle Scholar
  2. Bedwell, S., Dean, R. T., and Jessup, W. (1989) The action of defined oxygen-centred free radical on human low-density lipoprotein. Biochem. J. 262: 707–712.PubMedGoogle Scholar
  3. Boscoboinik, D., Szewczyk, A., Hensey, C., and Azzi, A. (1991) Inhibition of cell prohferation by a-tocopherol. J. Biol. Chem. 266: 6188–6194.PubMedGoogle Scholar
  4. Carew, T. E., Schwenke, D. C., and Steinberg, D. (1987) Antiatherogenic effect of probucal unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density hpoprotein 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.PubMedCrossRefGoogle Scholar
  5. Cazzolato, G., Avogaro, P., and Bittolo-Bon, G. (1991) Characterization of a more electroneg- atively charged LDL subfraction by ion exchange HPLC. Free Rad. Biol. Med. 11: 247–253.PubMedCrossRefGoogle Scholar
  6. Curzio, M., Esterbauer, H., Di Mauro, C., Cecchini, G., and Dianzani, M. U. (1986) Chemotactic activity of the Hpid peroxidation product 4-hydroxynonenal and homologous hydroxyalkenals. Biol. Chem. Hoppe-Seyler 367: 321–329.PubMedCrossRefGoogle Scholar
  7. Dieber-Rotheneder, M., Puhl, H., Wäg, 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 its oxidation resistance. J. Lipid Res. 8: 1325–1332.Google Scholar
  8. Esterbauer, H., Juergens, G., Quehenberger, O., and Koller, E. (1987) Autoxidation of human low density lipoprotein. Loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J. Lipid Res. 28: 495–509.PubMedGoogle Scholar
  9. Esterbauer, H., Quehenberger, O., and Juergens, G. (1988) Oxidation of human low density lipoprotein with special attention to aldehydic lipid peroxidation products, in: Free Radicals: Methodology and Concepts, pp. 243–268.Google Scholar
  10. Eds C. Rice-Evans and B. Halliwell. Richelieu Press, London.Google Scholar
  11. Esterbauer, H., Striegl, G., Puhl, H., and Rotheneder, M. (1989a) Continous monitoring of in vitro oxidation of human low density lipoprotein. Free Rad. Res. Commun. 6: 67–75.CrossRefGoogle Scholar
  12. Esterbauer, H., Zollner, H., and Schaur, R. J. (1989b) Aldehydes formed by lipid peroxidation: Mechanism of formation, occurrence and determination, in: Membrane Lipid Oxidation, vol. 1, pp. 239–268.Google Scholar
  13. Ed. C. Vigo-Pelfrey. CRC Press, Boca Raton.Google Scholar
  14. Esterbauer, H., Rotheneder, M., Waeg, G., Striedl, G., and Juergens, G. (1990a) Biochemical, structural, and functional properties of oxidized low-density lipoproteins. Chem. Res. Toxicol. 3: 77–92.PubMedCrossRefGoogle Scholar
  15. Esterbauer, H., Dieber-Rotheneder, M., Waeg, G., Puhl, H., and Tatzber, F. (1990b) Endogenous antioxidants and lipoprotein oxidation. Biochem. Soc. Trans. 18: 1059–1061.PubMedGoogle Scholar
  16. Esterbauer, H., Dieber-Rotheneder, M., Striegl, G., and Wäg, G. (1991a) Role of vitamin E in preventing the oxidation of low density hpoprotein. Am. J. Clin. Nutr. 53: 314S-321S.PubMedGoogle Scholar
  17. Esterbauer, H., Schaur, R. J., and Zollner, H. (1991b) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Rad. Biol. Med. 11: 81–128.PubMedCrossRefGoogle Scholar
  18. Esterbauer, H., Puhl, H., Dieber-Rotheneder, M., Waeg, G., and Rabl, H. (1991c) Effect of antioxidants on oxidative modification of LDL. Ann. Med. 23: 574–581.CrossRefGoogle Scholar
  19. Gaziano, J. M., Manson, J. E., Ridker, P. M., Buring, J. E., and Hennekens, C. H. (1990) Beta carotene for chronic stable angina. Circulation 82 (4 Suppl. Ill): 202.Google Scholar
  20. Gey, K. F., and Puska, P. (1989) Plasma vitamins E and A inversely related to mortality from ischemic heart disease in cross-cultural epidemiology. Ann. N.Y. Acad. Sci. 570: 268–282.PubMedCrossRefGoogle Scholar
  21. Gey, 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. CHn. Nutr. 53: 326S-334S.Google Scholar
  22. Haberland, M. E., Fogelman, A. M., and Edwards, P. A. (1982) Specificity of receptor-medi- ated recognition of malondialdehyde-modified low density lipoprotein. Proc. Natl. Acad. Sci. USA 79: 1712–1716.PubMedCrossRefGoogle Scholar
  23. Haberland, M. E., Fong, D., and Cheng, L. (1988) Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science 241: 215–218.PubMedCrossRefGoogle Scholar
  24. Harats, D., Ben-Naim, M., Dabach, Y., Hollander, G., Stein, O., and Stein, Y. (1989) Cigarette smoking renders LDL susceptible to peroxidative modification and enhanced metabolism by macrophages. Atherosclerosis 79: 245–252.PubMedCrossRefGoogle Scholar
  25. Hoff, H. F., Chisolm, G. M. Ill, Morel, D. W., Juergens, G., and Esterbauer, H. (1988) Chemical and functional changes in LDL following modification by 4-hydroxynonenal, in: oxy-Radicals Molecular Biology and Pathology, pp. 459–472.Google Scholar
  26. Eds P. A. Cerutti, J. M. McCord and T. Fridovich. Alan R. Liss, New York.Google Scholar
  27. Hoff, H. F., O’Neil, J., Chisolm, G. M., Cole, T. B., Quehenberger, O., Esterbauer, H., and Juergens, G. (1989) Modification of low-density lipoprotein with 4-hydroxynonenal induces uptake by macrophages. Arteriosclerosis 9: 538–549.PubMedCrossRefGoogle Scholar
  28. Janero, D. R. (1991) Therapeutic potential of vitamin E in the pathogenesis of spontaneous athersclerosis. Free Rad. Biol. Med. 11: 129–144.PubMedCrossRefGoogle Scholar
  29. Jessup, W., Rankin, S. M., De Whalley, C. V., Hoult, J. R. S., Scott, J., and Leake, D. S. (1990) Alpha-tocopherol consumption during low-density Hpoprotein oxidation. Biochem. J. 265: 399–405.PubMedGoogle Scholar
  30. Juergens, G., Hoff, H. F., Chisolm, G. M., and Esterbauer, H. (1987) Modification of human serum low density lipoprotein by oxidation-characterization and pathophysiological implications. Chem. Phys. Lipids. 45: 315–336.CrossRefGoogle Scholar
  31. Juergens, G., Ashy, A., and Esterbauer, H. (1990) Detection of new epitopes formed upon oxidation of low-density lipoprotein, lipoprotein (a) and very-low-density lipoprotein. Use of an antiserum against 4-hydroxynonenal-modified low-density lipoprotein. Biochem. J. 265: 605–608.Google Scholar
  32. Kaneko, T., Kaji, K., and Matsuo, M. (1988) Cytotoxicities of a linoleic acid hydroperoxide and its related aliphatic aldehydes toward cultured human umbilical vein endothelial cells. Chem.-Biol. Interact. 67: 295–304.PubMedCrossRefGoogle Scholar
  33. Kita, T., Nagano, Y., Yokode, M., Ishii, K., Kume, N., Narumiya, S., and Kawai, C. (1988) Prevention of atherosclerotic progession in Watanabe rabbits by probucol. Am. J. Cardiol. 62: 13B-19B.PubMedCrossRefGoogle Scholar
  34. Liu, S. K., Dolensek, E. P., and Tappe, J. P. (1984) Cardiomyopathy associated with vitamin E deficiency in seven gelada baboons. J. Am. Vet. Med. Assoc. 185: 1347–1350.PubMedGoogle Scholar
  35. Mino, M., Miki, M., Miyake, M., and Ogihara, T. (1989) Nutritional assessment of vitamin E in oxidative stress. Ann. N.Y. Acad. Sci. 570: 296–310.PubMedCrossRefGoogle Scholar
  36. Morel, D. W., DiCorleto, P. E., and Chisolm, G. M. (1984) Endothelial and smooth muscle cells alter low density hpoprotein in vitro by free radical oxidation. Arteriosclerosis 4: 357–364.PubMedCrossRefGoogle Scholar
  37. Morel, D. W., and Chisolm, G. M. (1989) Antioxidant treatment of diabetic rats inhibits Hpoprotein oxidation and cytotoxicity. J. Lipid Res. 30: 1827–1834.PubMedGoogle Scholar
  38. Palinski, W., Rosenfeld, M. E., Ylä-Herttuala, S., Gurtner, G. C., Socher, S. S., Butler, S. W., Parthasarathy, S., Carew, T. E., Steinberg, D., and Witztum, J. L. (1989) Low density Hpoprotein undergoes oxidative modification in vivo. Proc. Natl. Acad. Sci. USA 86: 1372–1376.PubMedCrossRefGoogle Scholar
  39. Parthasarathy, S., Young, S. G., Witztum, J. L., Pittman, R. C., and Steinberg, D. (1986) Probucol inhibits oxidative modification of low density Hpoprotein. J. CHn. Invest. 7: 641–644.CrossRefGoogle Scholar
  40. Quinn, M. T., Parthasarathy, S., Fong, L. G., and Steinberg, D. (1987) Oxidatively modified low density Hpoproteins: A potential role in recruitment and retention of monocyte/ macrophages during atherogenesis. Proc. Natl. Acad. Sci. USA 84: 2995–2998.PubMedCrossRefGoogle Scholar
  41. Riemersma, R. A., Wood, D. A., Macintyre, C. C. A., Elton, R. A., Gey, K. F., and Oliver, M. F. (1991) Risk of angina pectoris and plasma concentrations of vitamins A, C and E and carotene. Lancet 337: 1–5.PubMedCrossRefGoogle Scholar
  42. Rosenfeld, M. E., PaHnski, W., Ylä-Herttuala, S., Butler, S., and Witztum, J. L. (1990) Distribution of oxidation specific Hpid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis 10: 336–349.PubMedCrossRefGoogle Scholar
  43. Smith, T. L., and Kummerow, F. A. (1989) Effect of dietary vitamin E on plasma Hpids and atherogenesis in restricted ovulatory chickens. Atherosclerosis 75: 105–109.Google Scholar
  44. Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C., and Witztum, J. L. (1989) Beyond cholesterol. Modifications of low-density Hpoprotein that increase its atherogenicity. J. Engl. J. Med. 302: 915–924.Google Scholar
  45. Steinbrecher, U. P., Parathasarathy, S., Leake, D. S., Witztum J. L., and Steinberg, D. (1984) Modification of low density Hpoprotein by endothelial cells involves Hpid peroxidation and degradation of low density Hpoprotein phospholipids. Proc. Natl. Acad. Sci. USA 81: 3883–3887.Google Scholar
  46. Steinbrecher, U. P. (1987) Oxidation of human low density Hpoprotein results in derivatisa- tion of lysine residues of apolipoprotein B by Hpid peroxide decomposition products. J. Biol. Chem. 262: 3603–3608.PubMedGoogle Scholar
  47. Steinbrecher, U. P., Zhang, H., and Lougheed, M. (1990) Role of oxidatively modified LDL in atherosclerosis. Free Rad. Biol. Med. 9: 155–168.PubMedCrossRefGoogle Scholar
  48. Stocker, R., Bowry, V. W., and Frei, B. (1991) Ubiquinol-10 protects human low density Hpoprotein more efficiently against Hpid peroxidation than does a-tocopherol. Proc. Natl. Acad. Sci. USA 88: 1646–1650.PubMedCrossRefGoogle Scholar
  49. Tolonen, M., Sarna, S., Halme, M., Tuominen, S. E. J., Westermarck, T., Nordberg, U., Keinonen, M., and Schrijer, J. (1988) Antioxidant supplementation decreases TBA reac- tants in serum of elderly. Biol. Trace Element Res. 17: 221–228.CrossRefGoogle Scholar
  50. Veriangieri, A. J., and Bush, M. J. (1992) Eff’ects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J. Am. Coll. Nutr. 11: 131–138.Google Scholar
  51. Weitzel, G., Schön, H., Gey, K. F., and Buddecke, E. (1956) Lipid-soluble vitamins and atherosclerosis. Hoppe Seylers Z. Physiol. Chem. 304: 247–72CrossRefGoogle Scholar
  52. Westrope, K. L., Miller, R. A., and Wilson, R. B. (1982) Vitamin E in a rabbit model of endogenous hypercholesterolemia and atherosclerosis. Nutr. Reports Int. 25: 83–88.Google Scholar
  53. Wilson, R. B., Middleton, C. C., and Sun, G. Y. (1978) Vitamin E antioxidants and Hpid peroxidation in experimental atherosclerosis of rabbits. J. Nutr. 108: 1858–67.PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 1992

Authors and Affiliations

  • Hermann Esterbauer
    • 1
  • Georg Waeg
    • 1
  • Herbert Puhl
    • 1
  • M. Dieber-Rotheneder
    • 1
  • Franz Tatzber
    • 1
  1. 1.Institute of BiochemistryUniversity of GrazGrazAustria

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