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LDL oxidation by arterial wall macrophages depends on the oxidative status in the lipoprotein and in the cells: Role of prooxidants vs. antioxidants

  • Michael Aviram
  • Bianca Fuhrman
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 26)

Abstract

Oxidized LDL is highly atherogenic as it stimulates macrophage cholesterol accumulation and foam cell formation, it is cytotoxic to cells of the arterial wall and it stimulates inflammatory and thrombotic processes. LDL oxidation can lead to its subsequent aggregation, which further increases cellular cholesterol accumulation.

All major cells in the arterial wall including endothelial cells, smooth muscle cells and monocyte derived macrophages can oxidize LDL. Macrophage-mediated oxidation of LDL is probably a hallmark in early atherosclerosis, and it depends on the oxidative state of the LDL and that of the macrophages. The LDL oxidative state is elevated by increased ratio of poly/mono unsaturated fatty acids, and it is reduced by elevation of LDL-associated antioxidants such as vitamin E, ²-carotene, lycopene, and polyphenolic flavonoids.

The macrophage oxidative state depends on the balance between cellular NADPH -oxidase and the glutathione system. LDL-associated polyphenolic flavonoids which inhibit its oxidation, can also reduce macrophage oxidative state, and subsequently the cell-mediated oxidation of LDL. Oxidation of the macrophage lipids, which occurs under oxidative stress, can lead to cell-mediated oxidation of LDL even in the absence of transition metal ions, and may be operable in vivo.

Finally, elimination of Ox-LDL from extracellular spaces, after it was formed under excessive oxidative stress, can possibly be achieved by the hydrolytic action of HDL-associated paraoxonase on lipoprotein’s lipid peroxides. The present review article summarizes the above issues with an emphasis on our own data. (Mol Cell Biochem 188: 149–159, 1998)

Key words

atherosclerosis lipoproteins lipid peroxidation macrophages antioxidants polyphenols carotenoids 

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References

  1. 1.
    Aviram M: Oxidized low density lipoprotein (Ox-LDL) interaction with macrophages in atherosclerosis and the antiatherogenicity of antioxidants. Eur J Clin Chem Clin Biochem 34: 599–608, 1996PubMedGoogle Scholar
  2. 2.
    Aviram M: Oxidative modification of low density lipoprotein and atherosclerosis. Isr J Med Sci 31: 241–249, 1995PubMedGoogle Scholar
  3. 3.
    Aviram M: LDL-Platelet interaction under oxidative stress induces macrophage foam cell formation. Thromb Haemost 74(1): 560–564, 1995PubMedGoogle Scholar
  4. 4.
    Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL: Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320: 915–924, 1989PubMedCrossRefGoogle Scholar
  5. 5.
    Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al.: Atherosclerosis: Basic mechanisms. Oxidation, inflammation and genetics. Circulation 91: 2488–2498, 1995Google Scholar
  6. 6.
    Aviram M: The contribution of the macrophage receptor for oxidized LDL to its cellular uptake. Biochem Biophys Res Commun 179: 359–365, 1991PubMedCrossRefGoogle Scholar
  7. 7.
    Keidar S, Brook JG, Rosenblat M, Fuhrman B, Dankner G, Aviram M: Involvement of the macrophage LDL receptor binding domains in the uptake of oxidized LDL. Arterioscler Thromb Vasc Biol 12(4): 484–493, 1992CrossRefGoogle Scholar
  8. 8.
    Eisenberg S, Shayek E, Olivecrona T, Vlodavsky I: Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix. J Clin Invest 90: 2013–2021, 1992PubMedCrossRefGoogle Scholar
  9. 9.
    Williams KJ, Fless GM, Petrie KA, Snyder ML, Brocia RW, Swenson TL: Mechanisms by which lipoprotein lipase alters cellular metabolism of LP(a) LDL and nascent lipoporoteins. J Biol Chem 267: 13284–13292, 1992PubMedGoogle Scholar
  10. 10.
    Auerbach BJ, Bisgaier CL, Wolle J, Saxena U: Oxidation of low density lipoproteins greatly enhances their association with lipoprotein lipase anchored to endothelial cell matrix. J Biol Chem 271: 1329–1335, 1996PubMedCrossRefGoogle Scholar
  11. 11.
    Kaplan M, Williams JK, Mandel H, Aviram M: Role of macrophage glycosaminoglycans in the cellular catabolism of oxidized LDL by macrophages. Arterioscler Thromb Vasc Biol 18: 542–553, 1998PubMedCrossRefGoogle Scholar
  12. 12.
    Kaplan M, Aviram M: Oxidized LDL binding to a macrophage-secreted extracellular matrix. Biochem Biophys Res Commun 237: 271–276, 1997PubMedCrossRefGoogle Scholar
  13. 13.
    Aviram M, Maor I, Keidar S, Hayek T, Oiknine J, Bar-El Y, Adler Z, Kertzman V, Milo S: Lesioned low density lipoprotein in atherosclerotic apolipoprotein E deficient transgenic mice and in humans is oxidized and aggregated. Biochem Biophys Res Commun 216: 501–513, 1995PubMedCrossRefGoogle Scholar
  14. 14.
    Hayek T, Oiknine J, Brook JG, Aviram M: Increased plasma lipoprotein lipid peroxidation in apo E-deficient mice. Biochem Biophys Res Commun 201: 1567–1574, 1994PubMedCrossRefGoogle Scholar
  15. 15.
    Yla-Herttuala S, Palinski W, Rosenfeld ME, Pharthasarathy S, Carew TE, Buttler S, Witztum JL, Steinberg D: Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest 84: 10867–10895, 1989CrossRefGoogle Scholar
  16. 16.
    Haberland ME, Fogelman AM: The role of altered lipoprotein in the pathogenesis of atherosclerosis. Am Heart J 113: 573–577, 1987PubMedCrossRefGoogle Scholar
  17. 17.
    Lavy A, Brook JG, Dankner G, Ben Amotz A, Aviram M: Enhanced in vitro oxidation of plasma lipoproteins derived from hyper-cholesterolemic patients. Metabolism 40: 794–799, 1991PubMedCrossRefGoogle Scholar
  18. 18.
    Keidar S, Kaplan M, Shapira H, Brook JG, Aviram M: Low density lipoprotein isolated from patients with essential hypertension exhibits increased propensity for oxidation and enhanced uptake by macrophages: A possible role for angiotensin II. Atherosclerosis 104: 71–84, 1994CrossRefGoogle Scholar
  19. 19.
    Bergman R, Kasif Y, Aviram M, Maor I, Ullman Y, Gdal-on M, Friedman-Birnbaum R: Normolipidemic xanthelasma palpebrarum: Lipid composition, cholesterol metabolism in monocyte-derived macrophages, and plasma lipid peroxidation. Acta Derm Venereol 76: 107–110, 1996PubMedGoogle Scholar
  20. 20.
    Hussein O, Rosenblat M, Refael G, Aviram M: Dietary selenium increases cellular glutahtione peroxidase activity and reduces the enhanced susceptibility to lipid peroxidation of plasma and low density lipoprotein in kidney transplanted recipients. Transplantation 63: 679–685, 1997PubMedCrossRefGoogle Scholar
  21. 21.
    Pipek R, Dankner G, Ben-Amotz A, Aviram M, Levy Y: Increased plasma oxidizability in subjects with severe obesity. J Nutr Environ Med 6: 267–272, 1996CrossRefGoogle Scholar
  22. 22.
    Lavy A, Ben-Amotz A, Aviram M Increased susceptibility to lipid peroxidation of chylomicrons and low density lipoprotein in celiac disease. Ann Nutr Metabol 37: 68–74, 1993CrossRefGoogle Scholar
  23. 23.
    Maggi E, Bellazzi R, Gazo A, Secciam T, Bellomo G: Autoantibodies against oxidatively-modified LDL in chronic patients undergoing dialysis. Kidney Intern 46: 869–876, 1994CrossRefGoogle Scholar
  24. 24.
    Nishigaki I, Hagihara M, Tsunekana H, Maseki M, Yagi K: Lipid peroxide levels of serum lipoprotein fractions of diabetic patients. Biochem Med 25: 373–378, 1981PubMedCrossRefGoogle Scholar
  25. 25.
    Aviram M, Keidar S, Brook JG: Dual effect of lovastatin and simvastatin on LDL-macrophage interaction. Europ J Clin Chem Clin Biochem 29(10): 657–664, 1991Google Scholar
  26. 26.
    Aviram M, Dankner G, Cogan U, Hochgraf E, Brook JG: Lovastatin inhibits LDL oxidation and alters its fluidity and uptake by macrophages: In vitro and in vivo studies. Metabolism 41(3): 229–235, 1992PubMedCrossRefGoogle Scholar
  27. 27.
    Hoffman R, Brook JG, Aviram M: Hypolipidemic therapy reduces lipoprotein susceptibility to undergo lipid peroxidation: In vitro and ex vivo studies. Atherosclerosis 93: 105–113, 1992PubMedCrossRefGoogle Scholar
  28. 28.
    Hussein O, Schlezinger S, Rosenblat M, Keidar S, Aviram M: Reduced susceptibility of LDL to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL. Atherosclerosis 128: 11–18, 1997PubMedCrossRefGoogle Scholar
  29. 29.
    Aviram M, Hussein O, Rosenblat M, Schlezinger S, Hayek T, Keidar S: Interactions of platelets, macrophages and lipoproteins in hyper-cholesterolemia: Antiatherogenic effects of HMG-CoA reductase inhibitor therapy. J Cardiovasc Pharmacol 31: 39–45, 1998PubMedCrossRefGoogle Scholar
  30. 30.
    Aviram M, Rosenblat M, Bisgaier CL, Newton RS: Atorvastatin and gemfibrozil metabolises, but not the parent drugs are potent anti-oxidants against lipoproteins oxidation. Atherosclerosis (in press) 1998Google Scholar
  31. 31.
    Keidar S, Attias J, Smith J, Breslow JL, Hayek T: The angiotensin-II receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient mice. Biochem Biophys Res Commun 236(3): 622–625, 1997PubMedCrossRefGoogle Scholar
  32. 32.
    Aviram M, Kasem E: Dietary olive oil reduces the susceptibility of low density lipoprotein to lipid peroxidation and inhibits lipoprotein uptake by macrophages. Ann Nutr Metabol 37: 75–84, 1993CrossRefGoogle Scholar
  33. 33.
    Fuhrman B, Lavy A, Aviram M: Consumption of red wine with meals reduces the susceptibility of human plasma and LDL to undergo lipid peroxidation. Am J Clin Nutr 61: 549–554, 1995PubMedGoogle Scholar
  34. 34.
    Fuhrman B, Aviram M: White wine reduces LDL susceptibility to oxidation in vitro but not in vivo. Am J Clin Nutr 63: 403–404, 1996Google Scholar
  35. 35.
    Lavy A, Fuhrman B, Markel A, Dankner G, Ben Amotz A, Presser D Aviram M: The effect of dietary supplementation of red or white wine on human blood chemistry, hematology and coagulation pattern; favorable effect of red wine on plasma high density lipoprotein. Ann Nutr Metabol 38: 287–294, 1994CrossRefGoogle Scholar
  36. 36.
    Hayek T, Fuhrman B, Via J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M: Reduced progression of atherosclerosis in the apolipoprotein E deficient mice following consumption of red wine, or its polyphenols quercetin, or catechin, is associated with reduced susceptibility of LDL to oxidation and to aggregation. Arterioscler Thromb Vasc Biol 17: 2744–2752, 1997PubMedCrossRefGoogle Scholar
  37. 37.
    Vaya J, Belinky P, Aviram M: Antioxidant constituents from licorice roots: Isolation, structure elucidation and antioxidative capacity towards LDL oxidation. Free Radic Biol Med 23: 302–313, 1997PubMedCrossRefGoogle Scholar
  38. 38.
    Fuhrman B, Buch S, Vaya J, Belinky PA, Coleman R, Hayek T, Aviram M: Licorice extract and its major polyphenol glabridin protect LDL against lipid peroxidation: In vitro and ex-vivo studies in humans and in the atherosclerotic apolipoprotein E deficient mice. Am J Clin Nutr 66: 267–275, 1997PubMedGoogle Scholar
  39. 39.
    Rosenblat M, Aviram M: Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL. Free Radic Biol Med 24: 305–317, 1997CrossRefGoogle Scholar
  40. 40.
    Oiknine J, Aviram M: Increased susceptibility to activation and increased uptake of low density lipoprotein by cholesterol-loaded macrophages. Arterioscler Thromb Vasc Biol 12: 745–753, 1992CrossRefGoogle Scholar
  41. 41.
    Carter D, Fuhrman B, Aviram M: Macrophage activation with phorbol myristate acetate is associated with cellular lipid peroxidation. Isr J Med Sci 32(6): 479–485 1996PubMedGoogle Scholar
  42. 42.
    Hoff HF, O’Neil J: Lesion-derived low density lipoprotein and oxidized low density lipoprotein share a lability for aggregation, leading to enhanced macrophage degradation. Arterioscler Thromb 11: 1209–1222, 1991PubMedCrossRefGoogle Scholar
  43. 43.
    Meyer DF, Mayans MO, Groot PH, Suckling KE, Bruckdorfer KR, Perkins SJ: Time-course studies by neutron solution scattering and biochemical assays of the aggregation of human low-density lipoprotein during Cu2+-induced oxidation. Biochem J 310: 417–426, 1995PubMedGoogle Scholar
  44. 44.
    Maor I, Hayek T, Coleman R, Aviram M: Plasma LDL oxidation leads to its aggregation in the atherosclerotic apolipoprotein E deficient mice. Arterioscler Thromb Vasc Biol 17: 2995–3005, 1997PubMedCrossRefGoogle Scholar
  45. 45.
    Levy Y, Ben Amotz A, Dankner G, Brook JG, Aviram M: Enhanced lipid peroxidation of low density lipoprotein by fish oil. J Optimol Nutr 2: 6–9, 1993Google Scholar
  46. 46.
    Krinsky NI: Antioxidant functions of carotenoids. Free Radic Biol Med 7: 617–635, 1989PubMedCrossRefGoogle Scholar
  47. 47.
    Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R: Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334: 1145–1149, 1996PubMedCrossRefGoogle Scholar
  48. 48.
    Jialal I, Norkus EP, Cristor L, Grundy SM: ²-Carotene inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta 134–138, 1991Google Scholar
  49. 49.
    Sies W, Stahl W, Sundquist AR: Antioxidant functions of vitamins; vitamin E and C, Beta-carotene, and other carotenoids. In: H.E. Savberlich, L.Y. Machlin (eds). Beyond deficiency: New views on the function and health effects of vitamins. Ann NY Acad Sci 669: 7–20, 1992Google Scholar
  50. 50.
    Lavy A, Ben Amotz A, Aviram M: Preferential inhibition of LDL oxidation by the all-trans isomer of ²-carotene in comparison to the 9-cis-carotene. Eur J Clin Chem Clin Biochem 31: 83–90, 1993PubMedGoogle Scholar
  51. 51.
    Levy Y, Ben-Amotz A, Aviram M: Effect of dietary supplementation of ²-Carotene to humans on its binding to plasma LDL and on the lipoprotein susceptibility to undergo oxidative modification: Comparison of the synthetic all trans isomer with the natural algae ²-carotene. J Nutr Env Med 5: 13–22, 1995CrossRefGoogle Scholar
  52. 52.
    Levy Y, Kaplan M, Ben Amotz A, Aviram M: The effect of dietary supplementation of ²-carotene on human monocyte-macrophage-mediated oxidation of low density lipoprotein. Isr J Med Sci 32(6): 473–478, 1996PubMedGoogle Scholar
  53. 53.
    Fuhrman B, Ben-Yaish L, Attias J, Hayek T, Aviram M: Tomato’s lycopene and ²-carotene inhibit low density lipoprotein oxidation and this effect depends on the lipoprotein vitamin E content. Nutr Metab Cardiovasc Dis 7: 433–443, 1997Google Scholar
  54. 54.
    Chandler RF: Licorice, more than just a flavour. Can Pharm J 118: 420–424, 1985Google Scholar
  55. 55.
    Demizu S, Kajiyama K, Takahashi K, HiragaY, Yamamoto S, Tamura Y, Okada K, Kinoshita T: Antioxidant and antimicrobial constituents of Licorice: Isolation and structure elucidation of a new benzofuran derivative. Chem Pharm Bull 36: 3474–3479, 1988PubMedCrossRefGoogle Scholar
  56. 56.
    Aviram M, Rosenblat M: Macrophage-mediated oxidation of extracellular low density lipoprotein requires an initial binding of the lipoprotein to its receptor. J Lipid Res 35: 385–398, 1994PubMedGoogle Scholar
  57. 57.
    Aviram M, Rosenblat M, Etzioni A, Levy R: Activation of NADPH oxidase is required for macrophage-mediated oxidation of low density lipoprotein. Metabolism 45(9): 1069–1079, 1996PubMedCrossRefGoogle Scholar
  58. 58.
    Aviram M, Rosenblat M: Phospholipase A2 and phospholipase D are involved in macrophage NADPH oxidase-mediated oxidation of LDL. Isr J Med Sci 32: 749–756, 1996PubMedGoogle Scholar
  59. 59.
    Fuhrman B, Oiknine J, Aviram M: Iron induces lipid peroxidation in cultured macrophages increases their ability to oxidatively modify LDL and affect their secretory properties. Atherosclerosis 111: 65–78, 1994PubMedCrossRefGoogle Scholar
  60. 60.
    Keidar S, Kaplan M, Hoffman A, Brook JG, Aviram M: Angiotensin II stimulates macrophage-mediated lipid peroxidation of low density lipoprotein. Atherosclerosis 115: 201–215, 1995PubMedCrossRefGoogle Scholar
  61. 61.
    Ljubuncic P, Fuhrman B, Oiknine J, Aviram M, Bomzon A: The effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages. Gut 39: 475–478, 1996PubMedCrossRefGoogle Scholar
  62. 62.
    Fuhrman B, Oiknine J, Keidar S, Ben-Yaish L, Kaplan M, Aviram M: Increased uptake of LDL by oxidized macrophages is the result of an initial enhanced LDL receptor activity and of further progressive LDL oxidation. Free Radic Biol Med 23: 34–46, 1997PubMedCrossRefGoogle Scholar
  63. 63.
    Baker RD, Baker SS, LaRosa K: Selenium regulation of glutathione peroxidase in human hepatoma cell line Hep 3B. Arch Biochem Biophys 304: 53–57, 1993PubMedCrossRefGoogle Scholar
  64. 64.
    Kuzuya M, Natio M, Funakui C, Hayashi T, Asai K, Kuzuya F: Protective role of intracellular glutathione against oxidized low density lipoprotein in cultured endothelial cells. Biochem Biophys Res Commun 163(3): 1466–1472, 1989PubMedCrossRefGoogle Scholar
  65. 65.
    Gotoh N, Graham A, Niki E, Darly-Usmar UM; Inhibition of glutahtione synthesis increases the toxicity of oxidized low-density lipoprotein to human monocytes end macrophages. Biochem J 296: 151–154, 1994Google Scholar
  66. 66.
    Mackness MI, Abbott C, Arrol S, Durrington PN: The role of high density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J 294: 829–834, 1993PubMedGoogle Scholar
  67. 67.
    Hayek T, Oiknine J, Dankner G, Brook JG, Aviram M: HDL apolipo-protein A-I attenuates oxidative modification of low density lipoprotein: Studies in transgenic mice. Eur J Clin Chem Clin Biochem 33: 721–725, 1995PubMedGoogle Scholar
  68. 68.
    Mackness MI, Durrington PN: HDL, its enzymes and its potential to influence lipid peroxidation. Atherosclerosis 115: 243–253, 1995PubMedCrossRefGoogle Scholar
  69. 69.
    Mackness MI, Arrol S, Abbott C, Durrington PN: Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 104: 129–135, 1993PubMedCrossRefGoogle Scholar
  70. 70.
    Mackness MI, Arrol S: Durrington PN Paraoxonase prevents accumulation of lipoperoxides in low density lipoprotein. FEBS Lett 286: 152–154, 1991PubMedCrossRefGoogle Scholar
  71. 71.
    Navab M, Berliner JA, Watson AD, Hama SY, Teritto MC, Lusis AJ, Shih DM, Van Lenten DJ, Frank JS, Demer LL, Edwards PA, Fogelman AM: The Yin and Yang of oxidation in the development of the fatty streak. Arterioscler Thromb Vasc Biol 16: 831–842, 1996PubMedCrossRefGoogle Scholar
  72. 72.
    La Du BN: Structural and functional diversity of paraoxonases. Nature Medicine 2(11): 1186–1187, 1996PubMedCrossRefGoogle Scholar
  73. 73.
    Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA: Paraoxonase: Biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol 7: 69–76, 1996PubMedCrossRefGoogle Scholar
  74. 74.
    Mackness MI, Harty D, Bhatangar D, Winocour PH, Arrol S, Ishola M, Durrington PN: Serum Paraoxonase activity in familial hyper-cholesterolemia and insulin-dependent diabetes mellitus. Atherosclerosis 86: 193–199, 1991PubMedCrossRefGoogle Scholar
  75. 75.
    Abbott CA, Mackness MI, Kumar S, Boulton AJ, Durrington PN: Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vasc Biol 11: 1812–1818, 1995CrossRefGoogle Scholar
  76. 76.
    Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN: Paraoxonase inhibits high density lipoprotein (HDL) oxidation and preserves its functions: A possible peroxidative role for paraoxonase. J Clin Invest 101: 1581–1590, 1998PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Michael Aviram
    • 1
  • Bianca Fuhrman
    • 1
  1. 1.The Lipid Research Laboratory, Technion Faculty of MedicineThe Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical CenterHaifaIsrael

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