Modified Lipoproteins and Cardiovascular Risk

  • Waleed Aldahi
  • Jiri Frohlich
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 498)


It is generally accepted that LDL is the source of cholesterol accumulating in atherosclerotic lesions12. The precise mechanism of this accumulation remains to be It is generally accepted that LDL is the source of cholesterol accumulating in elucidated. Modified LDL, the subject of this article, is evolving as a significant link between lipoproteins and atherosclerosis3.


Foam Cell Scavenger Receptor Fatty Streak Heart Outcome Prevention Evaluation Iron Deficient Diet 
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  1. 1.
    Heinecke,JW. Oxidants and antioxidants in the pathogenesis of atherosclerosis: Implications for oxidized low density lipoprotein hypothesis. Atherosclerosis, 1998. 141: 1–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Navab, M; Berliner, JA; Watson, AB. et al. The yin and yang of oxidation in the development of the fatty streaks. A review based on the 1994 George Lyman Duff Memorial lecture. Arteriosclerosis. Thromb. Vase. Biol. July 1996. 16 (7): 831–842.CrossRefGoogle Scholar
  3. 3.
    Steinberg,D. and Witzman, JL. Lipoproteins and atherogenesis: current concepts. JAMA. 1990, 264: 3047–3052.PubMedCrossRefGoogle Scholar
  4. 4.
    Brown, M.S. and Goldstien J. A receptor mediated pathway for cholesterol homeostasis. L. Science. 1986, 232: 34–47.Google Scholar
  5. 5.
    Witzman JL and Steinberg D. Role of oxidized low-density lipoprotein in atherogenesis. J. Clin. Invest. December 1991. Volume 88, Pages: 1785–1792CrossRefGoogle Scholar
  6. 6.
    Hegele, R.A. The pathogenesis of atherosclerosis. Clinics. Chimica. Acta. 1996. 246: 21–38.CrossRefGoogle Scholar
  7. 7.
    Fogelman,A.M.; Schechter,J.S.; Hokom, M.; et al. Malondialdehyde alteration of low density lipoprotein leads to cholesterol accumulation in human monocyte-macrophages. Proc. Natl. Acad. Sci. U.S.A.. 1980, 77: 2214–2218.PubMedCrossRefGoogle Scholar
  8. 8.
    Heinecke,J.W.; Rosen, H.; Chait,A. Iron and copper promote modification of low-density lipoprotein by human arterial smooth muscle cells in culture. J. Clin. Invest.. 1987, 74: 1890–1894.Google Scholar
  9. 9.
    Henriksen, T.; Mahoney, E.M.; Steinberg, D. Enhanced degradation of low-density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated lowdensity lipoproteins. Proc. Natl. Acad. Sci. U.S.A.. 1981. 78: 6499–6503.PubMedCrossRefGoogle Scholar
  10. 10.
    Khoo, J.S.; Miller, E.; Mcloughlin, P.; Steinberg,D.. Enhanced macrophages uptake of low-density lipoprotein after self aggregation. Arteriosclerosis. 1988, 8: 348–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Hurt,E.; Camijo, G.. Effect of arterial protoglyns on the interaction of low-density lipoprotein with human monocyte-derived macrophages. Atherosclerosis. 1987, 67: 115–126.PubMedCrossRefGoogle Scholar
  12. 12.
    Horkko, S.; Miller, E.; Dudl, E. et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low-density lipoprotein. J. Clin. Invest..Aug. 1986. 98 (3): 815–25.CrossRefGoogle Scholar
  13. 13.
    Kodama, T; Freeman, M.; Rohrer, L. et al. Type 1 macrophage scavenger receptor contains alpha-helical and collagen like coiled coils. Nature. Feb. 8`h1990. 343 (6258): 513–5.CrossRefGoogle Scholar
  14. 14.
    Steinberg, D.. Low-density lipoprotein oxidation and its pathobiological significance. The journal of biological chemistry. Aug. 22“d1997. Vol. 272, No. 34: 20963–20966.Google Scholar
  15. 15.
    Cushing, SD; Berliner, JA; Valente, AJ, etal. Minimally modified low-density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscule cells. Proc. Natl. Acad. Sci. U.S.A. July 1990. 87 (13): 5134–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Steinberg, D.; Parthasarathy, T.E.; Carew,J. D. et al. Beyond cholesterol: Modifications of lowdensity lipoprotein that increase its atherogenecity. N. E. J. Med. 1989. 320: 915–924.CrossRefGoogle Scholar
  17. 17.
    Witztum, Joseph L. The oxidation hypothesis of atherosclerosis [Free radicals and antioxidants]. The Lancet. 17 sept. 1994. Vol. 344 (895): 793–795.Google Scholar
  18. 18.
    Lee, C.; Sigari, F.; Segrado, T. et al. All ApoB-containing lipoproteins induce monocyte chemotaxis and adhesion when minimally modified: Modulaton of lipoprotein bioactivity by platelet-activating factor acetylhydrolase [Atherosclerosis and Lipoproteins]. Arterioscler. Thromb. Vasc. Biol. June 1999, 19 (6):1437–1446.PubMedCrossRefGoogle Scholar
  19. 19.
    Jialal, I; Evolving lipoprotein risk factors: lipoprotein (a) and oxidized low-density lipoprotein. Clinical Chemistry. 1998. 44: 8(B); 1827–1832.PubMedGoogle Scholar
  20. 20.
    Steinberg, D. Oxidative modification of low-density lipoprotein and atherosclerosis. Lewis A. Conner memorial lecture. Circulation. Feb. 18`h1997. Vol 95 (4): 1062–1071.CrossRefGoogle Scholar
  21. 21.
    Steinberg, D. Low-density lipoprotein oxidation and its pathological significance. J. Biol. Chem. Aug.22nd1997. 272 (34): 20903–6.Google Scholar
  22. 22.
    Ross, R. The pathogenesis of atherosclerosis: A prospective for the 1990’s. Apr.29`h1993. 362 (6423): 801–9.Google Scholar
  23. 23.
    Esterbauer, H.; Wag, G.; Puhl, H. Lipid peroxidation and its role in atherosclerosis. Br. Med. Bull. July 1993.49 (3): 566–76.Google Scholar
  24. 24.
    Reinecke, J. W. Mechanism of oxidative damage of low-density lipoprotein in human atherosclerosis. Current Opinion in Lipidology. 1997. 8: 268–274.CrossRefGoogle Scholar
  25. 25.
    Esterbauer, H.; Gebicki, J.; Puhl, H.; Jurgens, G. The role of lipid peroxidation and oxidation in the oxidative modification of low-density lipoprotein. Free Radical Biol. Med. 1992; 13: 341–90.Google Scholar
  26. 26.
    Jurgens, G.;Hoff, H. F.; Chisolm III, G. M.; Esterbauer, H. Modification of human serum low-density lipoprotein by oxidation: Characterization and pathophysiological implications. Chem. Phys. Lipids. 1987; 45: 315–316.PubMedCrossRefGoogle Scholar
  27. 27.
    Superko, H. R. Small dense low-density lipoprotein subclass pattern B: Issues for clinicians. Current atherosclerosis reports. July 1999, Vol. 1, No. l : 50–57.PubMedCrossRefGoogle Scholar
  28. 28.
    Sullivan, J. L. Iron versus cholesterol: prospectives on the iron and heart disease debate. J Clin. Epidemiol. 1996; 49: 1345–1352.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee, F.Y.; Lee, T. S.; Pan, C. C. et al. Colocalization of iron and ceroid in human atherosclerotic lesions. Atherosclerosis. 1998; 138:281–288.PubMedCrossRefGoogle Scholar
  30. 30.
    Gillum, R. F. Body iron stores and atherosclerosis. Circulation 1997; 96: 3261–3263.PubMedGoogle Scholar
  31. 31.
    Lee, T. S.; Shiao, M. S.; Pan, C. C.; chau, L. Y. Iron deficient diet reduces atherosclerotic lesions in Apo E-deficient mice. Circulation. 1999; 99: 1222–1229.PubMedCrossRefGoogle Scholar
  32. 32.
    Roset, M.; Van der Schouw, Y. T.; de Valk, B. et al. Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation. 1999; 100:1268–1273.CrossRefGoogle Scholar
  33. 33.
    Tuomainen, T.; Kontula, K.; Nyyssönen, K. et al. Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cyst282Tyr mutation: a prospective cohort study in men in eastern Finland. Circulation. 1999; 100: 1274–1279.PubMedCrossRefGoogle Scholar
  34. 34.
    Acton, S. L.; Scherer, P. E.; Lodish, H. F.; Krieger, M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J. Biol. Chem. Aug. 19th1994; 269 (33): 21003–21009.Google Scholar
  35. 35.
    Frostegard, J.; Nilsson, J.; Hargerstrand, A. et al. Oxidized low-density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc. Natl. Acad. Sci. U.S.A. Feb. 1990; 87 (3): 904–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Berliner, J. A.; Navab, M.; Fogelman, A. M. et al. Atherosclerosis: basic machanisms, oxidation, inflamation and genetics. Circulation 1995; 91: 2488–96.PubMedCrossRefGoogle Scholar
  37. 37.
    Quinn, M. T.; Parthasarathy, S.; Fong, L. G.; Steinberg, D. Oxidatively modified low-density lipoproteins. A potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc. Natl. Acad. Sci. U.S.A. May 1987; 84 (9): 2995–8.CrossRefGoogle Scholar
  38. 38.
    Chatterjee, S. Ghosh, N. Oxidized low-density lipoprotein stimulates aortic smooth muscle proliferation. Glycobiology. Apr. 1996; 6 (3): 303–11.PubMedCrossRefGoogle Scholar
  39. 39.
    Kugiyama, K.; Kerns, S. A.; Morrisett, J. D. et al. Impairment of endothilium-dependant arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature. Mar. 8`h1990; 344(6262): 160–2.Google Scholar
  40. 40.
    Hoppe, G.; O’Neil, J.; Hoff, H. F. Inactivation of lysosomal proteases by oxidized low-density lipoprotein is partially responsible for its poor degradation by macrophages. J. Clin. Invest. 1994; 94: 1506–1512.PubMedCrossRefGoogle Scholar
  41. 41.
    O’Neil, J.; Hoppe, G.; Sayre, L. M.; Hoff, H. F. Inactivation of cathepsin B by oxidized low-density lipoprotein involves complex formation induced by binding of putative reaction sites exposed at low PH to thiols on the enzyme. Free Radical. Biol. Med. 1997; 23: 215–225.CrossRefGoogle Scholar
  42. 42.
    Harrison, D. G. Cellular and molecular mechanisms of endothelial cell dysfunction. J. of Clin. Invest. Nov.1’ 1997; Vol. 100 (9): 2153–2157.CrossRefGoogle Scholar
  43. 43.
    Posch, K.; Simecek, S.; Wascher, T. C. et al. Glycated low-density lipoprotein attenuates shear stress-induced nitric oxide synthesis by inhibition of shear stress-activated L-arginine uptake in endothelial cells. Diabetes. June 1999; 48 (6): 1331–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Ito, A.; Tsao, Ps.; Adimoolam, S.; Kimoto, M. et al. Novel mechanisms for endothelial dysfunction: dysregulation of dimethylarginine dimethyle aminohydrolase. Circulation. June 22nd1999; 99 (24): 3092–5.CrossRefGoogle Scholar
  45. 45.
    Stroes, E.; de Bruin, T.; de Valk, H. et al. NO activity in familial combined hyperlipidemia: potential role of cholesterol remnants. Cardiovascular Research. Dec. 1997; 36 (3): 445–52.PubMedCrossRefGoogle Scholar
  46. 46.
    Salonen, J.; Nyyssönen, K. Salonen, R. et al. Lipoprotein oxidation and progression of carotid atherosclerosis. Circulation. 1997; 95: 840–845.PubMedCrossRefGoogle Scholar
  47. 47.
    Yla-Herttuala, S.; Palinski, W. ;Rosenfeld, ME. Et al. Lipoproteins in normal and atherosclerotic aorta. Eur. Heart J. 1990; 11 (suppE): 88–99.PubMedCrossRefGoogle Scholar
  48. 48.
    Yla-Herttuala, S.; Palinski, W.; Rosenfeld, ME. Et al. Evidence for the presence of oxidatively modified low-density lipoprotein in atherosclerotic lesions of rabbit and man. J. Clin. Invest. 1989; 84: 1086–1095.PubMedCrossRefGoogle Scholar
  49. 49.
    Palinski, W.; Rosenfeld, ME.; Yla-Herttuala, S. et al. Low-density lipoprotein undergoes oxidative modification in vivo. Proc. Natl. Acad. Sci. U.S.A. Feb. 1989; 86 (4): 1372–6.CrossRefGoogle Scholar
  50. 50.
    Esterbauer, H.; Rothender, M.; Striegl, G. et al. Vitamin E and other lipophilic antioxidants protect low-density lipoprotein against oxidation. Fat. Sci. Technol. 1989: 9183–24.Google Scholar
  51. 51.
    Zieden, B; Kaminskas, A.; Kristenson, M. et al. Increased plasma 7 beta-hydroxycholesterol concentrations in a population with a high risk for cardiovascular disease. Arteriosclerosis, Thrombosis and Vascular Biology. Apr. 1999; 19 (4): 967–71.CrossRefGoogle Scholar
  52. 52.
    Omenn, GS; Goodman, GE; Thornquist, MD, et al. Effects of a combination of beta-carotene and retinol on lung cancer and cardiovascular disease. N.E. J. Med. 1996; 334: 1150–55.CrossRefGoogle Scholar
  53. 53.
    Hennekens, CH; Buring, JE; Manson, JE, et al. Lack of effect of long term supplementation with beta-carotene on the incidence of malignant neoplasmes and cardiovascular disease. N.E. J. Med. 1996;334: 1145–49.CrossRefGoogle Scholar
  54. 54.
    Rapola, JM; Virtamo, J; Haukka, JK, et al. Effects of vitamin E and beta-carotene on the incidence of angina pectoris: a randomized double blind controlled trial. JAMA. 1996; 275: 693–8.Google Scholar
  55. 55.
    Spencer, AP; Carson, DS; Crouch, MA. Vitamin E and coronary artery disease. Archives of Internal Medicine, 1999; Vol. 159 (12): 1313–1320.PubMedCrossRefGoogle Scholar
  56. 56.
    Hodis, HN; Mack, WJ; LaBree, L, et al.Serial coronary angiographie evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA. 1995; 273: 1849–1854.PubMedCrossRefGoogle Scholar
  57. 57.
    Stephens, N. G.; Parsons, A.; Schofeild, P. M.; et al. Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). The Lancet. March 23`d1996. Vol. 347: 781–786.Google Scholar
  58. 58.
    Marchioli, R.; Di Pasquale, A. I1 quadro di riferimento biochimico, farmacologico, epidemiologico del GISSI-prevenzione. G Ital Cardiol. 1993; 23: 933–64.PubMedGoogle Scholar
  59. 59.
    Ballantyne, C. M. Reducing atherothrombotic events in high-risk patients: recent data on therapy with statins and fatty acids. Current atherosclerosis reports. July 1999; Vol.1 No.1: 6–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Rapola, JM; Virtamo, J; Ripatti, S.; et al. Effects of alpha-tocopherol and beta-carotene supplementations on symptoms, progression and prognosis of angina pectoris. Heart. 1998; 79: 454458.Google Scholar
  61. 61.
    Rapola, JM; Virtamo, J; Ripatti, S.; et al. Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. The Lancet. 1997; 349: 1715–1720.CrossRefGoogle Scholar
  62. 62.
    The Hope study investigators. The HOPE (Heart Outcomes Prevention Evaluation) study. Can. J. Cardiol. Feb. 1996; 12 (2): 127–37.Google Scholar
  63. 63.
    Loran, E. M.; Yusuf, S. Evidence based cardiology: Emerging approaches in preventing cardiovascular disease. BMJ. May 1“ 1999. Vol. 318 (7194): 1337–1341.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Waleed Aldahi
    • 1
  • Jiri Frohlich
    • 1
  1. 1.Healthy Heart Program St. Paul’s HospitalUniversity of British ColombiaVancouverCanada

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