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Immunologic Research

, Volume 30, Issue 1, pp 73–80 | Cite as

The role of complement activation in atherosclerosis

  • Florin Niculescu
  • Horea RusEmail author
Article

Abstract

Atherosclerosis is a chronic inflammatory disease in which dyslipidemia, inflammation, and the immune system play an important pathogenetic role. A role in atherogenesis was demonstrated for monocyte/macrophages, complement system, and T-lymphocytes. Complement activation and C5b-9 deposition occurs both in human and experimental atherosclerosis. Complement C6 deficiency has a protective effect on diet-induced atherosclerosis, indicating that C5b-9 assembly is required for the progression of atherosclerotic lesions. The maturation of atherosclerotic lesions beyond the foam cell stage was shown to be strongly dependent on an intact complement system. C5b-9 may be responsible for cell lysis, and sublytic assembly of C5b-9 induces smooth muscle cell (SMC) and endothelial cell (EC) activation and proliferation. All these data suggest that activation of the complement system plays an important role in atherogenesis.

Key Words

Complement system Atherosclerosis Smooth muscle cells Endothelial cells C5b-9 terminal complement complex 

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References

  1. 1.
    Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–126.PubMedCrossRefGoogle Scholar
  2. 2.
    Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis. Nat Med 2002;8:1218–1226.PubMedCrossRefGoogle Scholar
  3. 3.
    Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res 2002;91:281–291.PubMedCrossRefGoogle Scholar
  4. 4.
    Niculescu F, Rus H. Complement activation and atherosclerosis. Mol Immunol 1999;36:949–955.PubMedCrossRefGoogle Scholar
  5. 5.
    Klouche M, Gottschling S, Gerl V, et al. Atherogenic properties of enzymatically degraded LDL: selective induction of MCP-1 and cytotoxic effects on human macrophages. Arterioscler Thromb Vasc Biol 1998;18:1376–1385.PubMedGoogle Scholar
  6. 6.
    Frank MM. Complement system; In Samter’s Immunologic Diseases. Frank MM AK, Claman HN, Unanue ER, eds. Little, Brown and Company, Boston, 1995, pp. 331–362.Google Scholar
  7. 7.
    Shin ML, Rus HG, Niculescu FI. Membranes Attack by Complement: Assembly and Biology of the Terminal Complement Complexes; in Biomembranes, AG Lee, ed. JAI Press, Greenwich, CT, 1996, vol. 4, pp 123–149.Google Scholar
  8. 8.
    Vlaicu R, Rus HG, Niculescu F, Cristea A. Quantitative determinations of immunoglobulins and complement components in human aortic atherosclerotic walls. Med Interne 1985;23:29–35.PubMedGoogle Scholar
  9. 9.
    Seifert PS, Hansson GK. Decay-accelerating factor is expressed on vascular smooth muscle cells in human atherosclerotic lesions. J Clin Invest 1989;84:597–604.PubMedGoogle Scholar
  10. 10.
    Seifert PS, Hansson GK. Complement receptors and regulatory proteins in human atherosclerotic lesions. Arteriosclerosis 1989;9:802–811.PubMedGoogle Scholar
  11. 11.
    Niculescu F, Rus HG, Vlaicu R. Decay-accelerating factor regulates complement-mediated damage in the human atherosclerotic walls. Immunol Lett 1990;26:17–23.PubMedCrossRefGoogle Scholar
  12. 12.
    Niculescu F, Rus HG, Vlaicu R. Immunohistochemical localization of C5b-9, S-protein, C3d and apolipoprotein B in human arterials tissues with atherosclerosis. Atherosclerosis 1987;65:1–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Mackness B, Hunt R, Durrington PN, Mackness MI. Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:1233–1238.PubMedGoogle Scholar
  14. 14.
    Yasojima K, Schwab C, McGeer EG, McGeer PL. Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001;21:1214–1219.PubMedGoogle Scholar
  15. 15.
    Oksjoki R, Jarva H, Kovanen PT, Laine P, Meri S, Pentikainen MO. Association between complement factor h and proteoglycans in early human coronary atherosclerotic lesions: implications for local regulation of complement activation. Arterioscler Thromb Vasc Biol 2003;23:630–636.PubMedCrossRefGoogle Scholar
  16. 16.
    Niculescu F, Rus HG, Porutiu D, Ghiurca V, Vlaicu R. Immunoelectron-microscopic localization of S-protein/vitronectin in human atherosclerotic wall. Atherosclerosis 1989;78:197–203.PubMedCrossRefGoogle Scholar
  17. 17.
    Vlaicu R, Niculescu F, Rus HG, Cristea A. Immuno histochemical localization of the terminal C5b-9 complement complex in human aortic fibrous plaque. Atherosclerosis 1985;57:163–177.PubMedCrossRefGoogle Scholar
  18. 18.
    Niculescu F, Hugo F, Rus HG, Vlaicu R, Bhakdi S. Quantitative evaluation of the terminal C5b-9 complement complex by ELISA in human atherosclerotic arteries. Clin Exp Immunol 1987;69:477–483.PubMedGoogle Scholar
  19. 19.
    Rus HG, Niculescu F, Constantinescu E, Cristea A, Vlaicu R Immunoelectron-microscopic localization of the terminal C5b-9 complement complex in human atherosclerotic fibrous plaque. Atherosclerosis 1986;61:35–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Torzewski M, Klouche M, Hock J, et al. Immunohistochemical demonstration of enzymatically modified human LDL and its colocalization with the terminal complement complex in the early atherosclerotic lesion. Arterioscler Thromb Vasc Biol 1998;18:369–378.PubMedGoogle Scholar
  21. 21.
    Rus HG, Niculescu F, Porutiu D, Ghiurca V, Vlaicu R. Cells carrying C5b-9 complement complexes in human atherosclerotic wall. Immunol Lett 1989;20:305–310.PubMedCrossRefGoogle Scholar
  22. 22.
    Seifert PS, Roth I, Schmiedt W, et al. CD59 (homologous restriction factor 20), a plasma membrane protein that protects against complement C5b-9 attack, in human atherosclerotic lesions. Atherosclerosis 1992;96:135–145.PubMedCrossRefGoogle Scholar
  23. 23.
    Rus HG, Niculescu FI, Shin ML. Role of the C5b-9 complement complex in cell cycle and apoptosis. Immunol Rev 2001;180:49–55.PubMedCrossRefGoogle Scholar
  24. 24.
    Reynolds GD, Vance RP. C-reactive protein immuno-histochemical localization in normal and atherosclerotic human aortas. Arch Pathol Lab Med 1987;111:265–269.PubMedGoogle Scholar
  25. 25.
    Torzewski J, Torzewski M, Bowyer DE, et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 1998;18:1386–1392.PubMedGoogle Scholar
  26. 26.
    Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 2001;158:1039–1051.PubMedGoogle Scholar
  27. 27.
    Bhakdi S, Torzewski M, Klouche M, Hemmes M. Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol 1999;19:2348–2354.PubMedGoogle Scholar
  28. 28.
    Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci USA 2002;99:13043–13048.PubMedCrossRefGoogle Scholar
  29. 29.
    Xu Q, Kiechl S, Mayr M, et al.. Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis: clinical significance determined in a follow-up study. Circulation 1999;100:1169–1174.PubMedGoogle Scholar
  30. 30.
    Wieland E, Dorweiler B, Bonitz U, Lieser S, Walev I, Bhakdi S. Complement activation by oxidatively modified low-density lipoproteins. Eur J Clin Invest 1999;29:835–841.PubMedCrossRefGoogle Scholar
  31. 31.
    Seifert PS, Hugo F, Tranum-Jensen J, Zahringer U, Muhly M, Bhakdi S. Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions. J Exp Med 1990;172:547–557.PubMedCrossRefGoogle Scholar
  32. 32.
    Bhakdi S, Dorweiler B, Kirchmann R, et al. On the pathogenesis of atherosclerosis: enzymatic transformation of human low density lipoprotein to an atherogenic moiety. J Exp Med 1995;182:1959–1971.PubMedCrossRefGoogle Scholar
  33. 33.
    Klouche M, Rose-John S, Schmiedt W, Bhakdi S. Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell activation, foam cell transformation, and proliferation. Circulation 2000;101: 1799–1805.PubMedGoogle Scholar
  34. 34.
    Klouche M, May AE, Hemmes M, et al. Enzymatically modified, nonoxidized LDL induces selective adhesion and transmigration of monocytes and T-lymphocytes through human endothelial cell monolayers. Arterioscler Thromb Vasc Biol 1999;19:784–793.PubMedGoogle Scholar
  35. 35.
    Seifert PS, Kazatchkine MD. Generation of complement anaphylatoxins and C5b-9 by crystalline cholesterol oxidation derivatives depends on hydroxyl group number and position. Mol Immunol 1987;24:1303–1308.PubMedCrossRefGoogle Scholar
  36. 36.
    Simionescu N, Vasile E, Lupu F, Popescu G, Simionescu M. Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit. Am J Pathol 1986;123:109–125.PubMedGoogle Scholar
  37. 37.
    Pinckard RN, Olson MS, Giclas PC, Terry R, Boyer JT, O’Rourke RA. Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction. J Clin Invest 1975;56:740–750.PubMedGoogle Scholar
  38. 38.
    Megran DW, Stiver HG, Bowie WR. Complement activation and stimulation of chemotaxis by Chlamydia trachomatis. Infect Immun 1985;49:670–673.PubMedGoogle Scholar
  39. 39.
    Campbell LA, Kuo CC. Chlamydia pneumoniae and atherosclerosis. Semin Respir Infect 2003;18:48–54.PubMedCrossRefGoogle Scholar
  40. 40.
    Rugonfalvi-Kiss S, Endresz V, Madsen HO, et al. Association of Chlamydia pneumoniae with coronary artery disease and its progression is dependent on the modifying effect of mannose-binding lectin. Circulation 2002;106:1071–1076.PubMedCrossRefGoogle Scholar
  41. 41.
    Geertinger P, Sorensen H. Complements as a factor in arteriosclerosis. Acta Pathol Microbiol Scand [A] 1970;78:284–288.Google Scholar
  42. 42.
    Schmiedt W, Kinscherf R, Deigner HP, et al. Complement C6 deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 1998;18:1790–1795.PubMedGoogle Scholar
  43. 43.
    Patel S, Thelander EM, Hernandez M, et al. ApoE(−/−) mice develop atherosclerosis in the absence of complement component C5. Biochem Biophys Res Commun 2001;286:164–170.PubMedCrossRefGoogle Scholar
  44. 44.
    Buono C, Come CE, Witztum JL, et al. Influence of C3 deficiency on atherosclerosis Circulation 2002;105:3025–3031.PubMedCrossRefGoogle Scholar
  45. 45.
    Morgan BP, Dankert JR, Esser AF. Recovery of human neutrophils from complement attack: removal of the membrane attack complex by endocytosis and exocytosis. J Immunol 1987;138:246–253.PubMedGoogle Scholar
  46. 46.
    Ferguson JE 3rd, Patterson C. Break the cycle. Cell Cycle 2003;2:211–219.PubMedGoogle Scholar
  47. 47.
    Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 1995;75:487–517.PubMedGoogle Scholar
  48. 48.
    Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 1996;87:1069–1078.PubMedCrossRefGoogle Scholar
  49. 49.
    Torzweski M, Torzewski J, Bowyer DE, et al. Immuno-histochemical colocalization of the terminal complex of human complement and smooth muscle cell alpha-actin in early atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1997;17:2448–2452.Google Scholar
  50. 50.
    Niculescu F, Badea T, Rus H. Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase. Atherosclerosis 1999;142:47–56.PubMedCrossRefGoogle Scholar
  51. 51.
    Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999;13:1501–1512.PubMedGoogle Scholar
  52. 52.
    Badea T, Niculescu F, Soane L, et al. RGC-32 increases p34CDC2 kinase activity and entry of aortic smooth muscle cells into S-phase. J Biol Chem 2002;277:502–508.PubMedCrossRefGoogle Scholar
  53. 53.
    Torzewski J, Oldroyd R, Lachmann P, Fitzsimmons C, Proudfoot D, Bowyer D. Complement-induced release of monocyte chemotactic protein-1 from human smooth muscle cells. A possible initiating event in atherosclerotic lesion formation. Arterioscler Thromb Vasc Biol 1996;16:673–677.PubMedGoogle Scholar
  54. 54.
    Hunt BJ. The endothelium in atherogenesis. Lupus 2000;9:189–193.PubMedCrossRefGoogle Scholar
  55. 55.
    Brasen JH, Kivela A, Roser K, et al. Angiogenesis, vascular endothelial growth factor and platelet-derived growth factor-BB expression, iron deposition, and oxidation-specific epitopes in stented human coronary arteries. Arterioscler Thromb Vasc Biol 2001;21:1720–1726.PubMedGoogle Scholar
  56. 56.
    Christiansen VJ, Sims PJ, Hamilton KK. Complement C5b-9 increases plasminogen binding and activation on human endothelial cells. Arterioscler Thromb Vasc Biol 1997;17:164–171.PubMedGoogle Scholar
  57. 57.
    Tran GT, Hodgkinson SJ, Carter N, Killingsworth M, Spicer ST, Hall BM. Attenuation of experimental allergic encephalomyelitis in complement component 6-deficient rats is associated with reduced complement C9 deposition, P-selection expression, and cellular infiltrate in spinal cords. J Immunol 2002;168:4293–4300.PubMedGoogle Scholar
  58. 58.
    Kilgore KS, Schmid E, Shanley TP, et al. Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation. Am J Pathol 1997;150:2019–2031.PubMedGoogle Scholar
  59. 59.
    Kilgore KS, Shen JP, Miller BF, Ward PA, Warren JS. Enhancement by the complement membrane attack complex of tumor necrosis factor-alpha-induced endothelial cell expression of E-selectin and ICAM-1. J Immunol 1995;155:1434–1441.PubMedGoogle Scholar
  60. 60.
    Saadi S, Holzknecht RA, Patte CP, Platt JL. Endothelial cell activation by poreforming structures: pivotal role for interleukin-1alpha. Circulation 2000;101:1867–1873.PubMedGoogle Scholar
  61. 61.
    Halperin JA, Taratuska A, Nicholson-Weller A. Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells. J Clin Invest 1993;91:1974–1978.PubMedCrossRefGoogle Scholar
  62. 62.
    Niculescu F, Soane L, Badea T, Shin M, Rus H. Tyrosine phosphorylation and activation of Janus kinase 1 and STAT3 by sublytic C5b-9 complement complex in aortic endothelial cells. Immunopharmacology 1999;42:187–193.PubMedCrossRefGoogle Scholar
  63. 63.
    Niculescu F, Hila S, Fosbrik M, et al. Endothelial cell proliferation induced by sublytic C5b-9 requires the activation of p70S6 kinase through a mechanisms involving the G-protein dependent activation of phosphatidy lynositol 3-kinase. International Immunopharmacology 2002;318:1219A.Google Scholar
  64. 64.
    Tenaglia AN, Peters KG, Sketch MH, Jr., Annex BH. Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J 1998;135:10–14.PubMedCrossRefGoogle Scholar
  65. 65.
    Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest 1999;103:1231–1236.PubMedGoogle Scholar
  66. 66.
    Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analysis. Circulation 1998;98:224–233.PubMedGoogle Scholar
  67. 67.
    Gousseva N, Kugathasan K, Chesterman CN, Khachigian LM. Early growth response factor-1 mediates insulin-inducible vascular endothelial cell proliferation and regrowth after injury J Cell Biochem 2001;81:523–534.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Maryland School of MedicineBaltimore

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