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The role of complement activation in atherogenesis: the first 40 years

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Abstract

The pathogenesis of atherosclerotic inflammation is a multi-step process defined by the interweaving of excess modified lipid particles, monocyte-macrophages populations, and innate immune and adaptive immunity effectors. A part of innate immunity, the complement system, is an important player in the induction and progression of atherosclerosis. The accumulation of either oxidized or enzymatically modified LDL—bound to C-reactive protein or not—prompts complement activation leading to the assembly of the terminal complement C5b-9 complex in the atherosclerotic lesion. The sublytic C5b-9 assembly leads to the activation and proliferation of smooth muscle and endothelial cells, accompanied by the release of various chemotactic, pro-adhesion, and procoagulant cytokines from these cells. Response gene to complement (RGC)-32, an essential effector of the terminal complement complex C5b-9, also affects atherogenesis, propelling vascular smooth muscle cell proliferation and migration, stimulating endothelial proliferation, and promoting vascular lesion formation. A substantial amount of experimental work has suggested a role for the complement system activation during atherosclerotic plaque formation, with the proximal classical complement pathway seemingly having a protective effect and terminal complement contributing to accelerated atherogenesis. All these data suggest that complement plays an important role in atherogenesis.

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References

  1. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204–12.

    Article  PubMed  CAS  Google Scholar 

  2. Hansson GK. Atherosclerosis—an immune disease: the Anitschkov Lecture 2007. Atherosclerosis. 2009;202:2–10.

    Article  PubMed  CAS  Google Scholar 

  3. Niculescu F, Rus H. Complement activation and atherosclerosis. Mol Immunol. 1999;36:949–55.

    Article  PubMed  CAS  Google Scholar 

  4. Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J. 2010;74:213–20.

    Article  PubMed  CAS  Google Scholar 

  5. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473:317–25.

    Article  PubMed  CAS  Google Scholar 

  6. Torzewski M, Bhakdi S. Complement and atherosclerosis-united to the point of no return? Clin Biochem. 2013;46:20–5.

    Article  PubMed  CAS  Google Scholar 

  7. Niculescu F, Rus H. The role of complement activation in atherosclerosis. Immunol Res. 2004;30:73–80.

    Article  PubMed  CAS  Google Scholar 

  8. Geertinger P, Soerensen H. On the reduced atherogenic effects of cholesterol feeding on rabbits with congenital complement (C6) deficiency. Artery. 1977;1:177–84.

    Google Scholar 

  9. Tegla CA, Cudrici C, Patel S, Trippe R 3rd, Rus V, Niculescu F, Rus H. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res. 2011;51:45–60.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20:34–50.

    Article  PubMed  CAS  Google Scholar 

  11. Vlaicu R, Rus HG, Niculescu F, Cristea A. Quantitative determinations of immunoglobulins and complement components in human aortic atherosclerotic wall. Med Interne. 1985;23:29–35.

    PubMed  CAS  Google Scholar 

  12. 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;17:1233–8.

    Article  PubMed  CAS  Google Scholar 

  13. Niculescu F, Rus HG, Vlaicu R. Immunohistochemical localization of C5b-9, S-protein, C3d and apolipoprotein B in human arterial tissues with atherosclerosis. Atherosclerosis. 1987;65:1–11.

    Article  PubMed  CAS  Google Scholar 

  14. Niculescu F, Rus HG, Vlaicu R. Decay-accelerating factor regulates complement-mediated damage in the human atherosclerotic wall. Immunol Lett. 1990;26:17–23.

    Article  PubMed  CAS  Google Scholar 

  15. Seifert PS, Hansson GK. Complement receptors and regulatory proteins in human atherosclerotic lesions. Arteriosclerosis. 1989;9:802–11.

    Article  PubMed  CAS  Google Scholar 

  16. Seifert PS, Hansson GK. Decay-accelerating factor is expressed on vascular smooth muscle cells in human atherosclerotic lesions. J Clin Investig. 1989;84:597–604.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Yasojima K, Schwab C, McGeer EG, McGeer PL. Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001;21:1214–9.

    Article  PubMed  CAS  Google Scholar 

  18. Cao W, Bobryshev YV, Lord RS, Oakley RE, Lee SH, Lu J. Dendritic cells in the arterial wall express C1q: potential significance in atherogenesis. Cardiovasc Res. 2003;60:175–86.

    Article  PubMed  CAS  Google Scholar 

  19. Oksjoki R, Kovanen PT, Mayranpaa MI, Laine P, Blom AM, Meri S, Pentikainen MO. Complement regulation in human atherosclerotic coronary lesions. Immunohistochemical evidence that C4b-binding protein negatively regulates the classical complement pathway, and that C5b-9 is formed via the alternative complement pathway. Atherosclerosis. 2007;192:40–8.

    Article  PubMed  CAS  Google Scholar 

  20. Vlaicu R, Niculescu F, Rus HG, Cristea A. Immunohistochemical localization of the terminal C5b-9 complement complex in human aortic fibrous plaque. Atherosclerosis. 1985;57:163–77.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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;23:630–6.

    Article  PubMed  CAS  Google Scholar 

  23. Reynolds GD, Vance RP. C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas. Arch Pathol Lab Med. 1987;111:265–9.

    PubMed  CAS  Google Scholar 

  24. Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, Waltenberger J, Fitzsimmons C, Hombach V. 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;18:1386–92.

    Article  PubMed  CAS  Google Scholar 

  25. Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol. 2001;158:1039–51.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. 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;99:13043–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Bhakdi S, Torzewski M, Paprotka K, Schmitt S, Barsoom H, Suriyaphol P, Han SR, Lackner KJ, Husmann M. Possible protective role for C-reactive protein in atherogenesis: complement activation by modified lipoproteins halts before detrimental terminal sequence. Circulation. 2004;109:1870–6.

    Article  PubMed  CAS  Google Scholar 

  28. 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;19:2348–54.

    Article  PubMed  CAS  Google Scholar 

  29. 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;69:477–83.

    PubMed Central  PubMed  CAS  Google Scholar 

  30. Niculescu F, Rus HG, Vlaicu R. Activation of the human terminal complement pathway in atherosclerosis. Clin Immunol Immunopathol. 1987;45:147–55.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Rus HG, Niculescu F, Porutiu D, Ghiurca V, Vlaicu R. Cells carrying C5b-9 complement complexes in human atherosclerotic wall. Immunol Lett. 1989;20:305–10.

    Article  PubMed  CAS  Google Scholar 

  33. Torzewski M, Klouche M, Hock J, Messner M, Dorweiler B, Torzewski J, Gabbert HE, Bhakdi S. 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;18:369–78.

    Article  PubMed  CAS  Google Scholar 

  34. Meuwissen M, van der Wal AC, Niessen HW, Koch KT, de Winter RJ, van der Loos CM, Rittersma SZ, Chamuleau SA, Tijssen JG, Becker AE, Piek JJ. Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction. J Clin Pathol. 2006;59:196–201.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Rus HG, Niculescu F, Vlaicu R. Co-localization of terminal C5b-9 complement complexes and macrophages in human atherosclerotic arterial walls. Immunol Lett. 1988;19:27–32.

    Article  PubMed  CAS  Google Scholar 

  36. Rus HG, Niculescu FI, Shin ML. Role of the C5b-9 complement complex in cell cycle and apoptosis. Immunol Rev. 2001;180:49–55.

    Article  PubMed  CAS  Google Scholar 

  37. Tulamo R, Frosen J, Paetau A, Seitsonen S, Hernesniemi J, Niemela M, Jarvela I, Meri S. Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation. Am J Pathol. 2010;177:3224–32.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Mourani PM, Garl PJ, Wenzlau JM, Carpenter TC, Stenmark KR, Weiser-Evans MC. Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6 K signaling and is actively repressed by PTEN. Circulation. 2004;109:1299–306.

    Article  PubMed  CAS  Google Scholar 

  39. Torzewski M, Torzewski J, Bowyer DE, Waltenberger J, Fitzsimmons C, Hombach V, Gabbert HE. Immunohistochemical colocalization of the terminal complex of human complement and smooth muscle cell alpha-actin in early atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 1997;17:2448–52.

    Article  PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. Bertoli C, Skotheim JM, de Bruin RA. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol. 2013;14:518–28.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Lange M, Fujikawa T, Koulova A, Kang S, Griffin MJ, Lassaletta AD, Erat A, Tobiasch E, Bianchi C, Elmadhun N, Sellke FW, Usheva A. Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens. Cell Cycle. 2014;13:315–23.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Ferguson JE 3rd, Patterson C. Break the cycle: the role of cell-cycle modulation in the prevention of vasculoproliferative diseases. Cell Cycle. 2003;2:211–9.

    Article  PubMed  CAS  Google Scholar 

  44. 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;16:673–7.

    Article  PubMed  CAS  Google Scholar 

  45. Niu J, Kolattukudy PE. Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications. Clin Sci. 2009;117:95–109 (Lond).

    Article  PubMed  CAS  Google Scholar 

  46. Zwaka TP, Torzewski J, Hoeflich A, Dejosez M, Kaiser S, Hombach V, Jehle PM. The terminal complement complex inhibits apoptosis in vascular smooth muscle cells by activating an autocrine IGF-1 loop. Faseb J. 2003;17:1346–8.

    PubMed  CAS  Google Scholar 

  47. Higashi Y, Sukhanov S, Anwar A, Shai SY, Delafontaine P. Aging, atherosclerosis, and IGF-1. J Gerontol A Biol Sci Med Sci. 2012;67:626–39.

    Article  PubMed  CAS  Google Scholar 

  48. Favero G, Paganelli C, Buffoli B, Rodella LF, Rezzani R. Endothelium and its alterations in cardiovascular diseases: life style intervention. Biomed Res Int. 2014;2014:801896.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem. 1988;263:18205–12.

    PubMed  CAS  Google Scholar 

  50. Hattori R, Hamilton KK, McEver RP, Sims PJ. Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface. J Biol Chem. 1989;264:9053–60.

    PubMed  CAS  Google Scholar 

  51. Rollins SA, Johnson KK, Li L, Birks C, Matis LA, Rother RP. Role of porcine P-selectin in complement-dependent adhesion of human leukocytes to porcine endothelial cells. Transplantation. 2000;69:1659–67.

    Article  PubMed  CAS  Google Scholar 

  52. Saadi S, Holzknecht RA, Patte CP, Stern DM, Platt JL. Complement-mediated regulation of tissue factor activity in endothelium. J Exp Med. 1995;182:1807–14.

    Article  PubMed  CAS  Google Scholar 

  53. Kilgore KS, Schmid E, Shanley TP, Flory CM, Maheswari V, Tramontini NL, Cohen H, Ward PA, Friedl HP, Warren JS. 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;150:2019–31.

    PubMed Central  PubMed  CAS  Google Scholar 

  54. 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;155:1434–41.

    PubMed  CAS  Google Scholar 

  55. Benzaquen LR, Nicholson-Weller A, Halperin JA. Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med. 1994;179:985–92.

    Article  PubMed  CAS  Google Scholar 

  56. Fosbrink M, Niculescu F, Rus V, Shin ML, Rus H. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J Biol Chem. 2006;281:19009–18.

    Article  PubMed  CAS  Google Scholar 

  57. Solvik UO, Haraldsen G, Fiane AE, Boretti E, Lambris JD, Fung M, Thorsby E, Mollnes TE. Human serum-induced expression of E-selectin on porcine aortic endothelial cells in vitro is totally complement mediated. Transplantation. 2001;72:1967–73.

    Article  PubMed  CAS  Google Scholar 

  58. Christiansen VJ, Sims PJ, Hamilton KK. Complement C5b-9 increases plasminogen binding and activation on human endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17:164–71.

    Article  PubMed  CAS  Google Scholar 

  59. Mason JC, Ahmed Z, Mankoff R, Lidington EA, Ahmad S, Bhatia V, Kinderlerer A, Randi AM, Haskard DO. Statin-induced expression of decay-accelerating factor protects vascular endothelium against complement-mediated injury. Circ Res. 2002;91:696–703.

    Article  PubMed  CAS  Google Scholar 

  60. Mason JC, Lidington EA, Yarwood H, Lublin DM, Haskard DO. Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis. Arthritis Rheum. 2001;44:138–50.

    Article  PubMed  CAS  Google Scholar 

  61. Mason JC, Yarwood H, Sugars K, Morgan BP, Davies KA, Haskard DO. Induction of decay-accelerating factor by cytokines or the membrane-attack complex protects vascular endothelial cells against complement deposition. Blood. 1999;94:1673–82.

    PubMed  CAS  Google Scholar 

  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. Immunopharmacol. 1999;42:187–93.

    Article  CAS  Google Scholar 

  63. Niculescu F, Hila S, Fosbrink M, Soane L, Popescu T, Shustova V, Rus V, Shin ML, Rus H. Endothelial cell proliferation induced by sublytic C5b-9 requires the activation of p70S6 kinase through a mechanism involving the G-protein dependent activation of phosphatidylinositol 3-kinase. Int Immunopharmacol. 2002;318:1219.

    Google Scholar 

  64. Kolodgie FD, Narula J, Yuan C, Burke AP, Finn AV, Virmani R. Elimination of neoangiogenesis for plaque stabilization: is there a role for local drug therapy? J Am Coll Cardiol. 2007;49:2093–101.

    Article  PubMed  CAS  Google Scholar 

  65. Mitra AK, Agrawal DK. In stent restenosis: bane of the stent era. J Clin Pathol. 2006;59:232–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. 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;135:10–4.

    Article  PubMed  CAS  Google Scholar 

  67. Badea TC, Niculescu FI, Soane L, Shin ML, Rus H. Molecular cloning and characterization of RGC-32, a novel gene induced by complement activation in oligodendrocytes. J Biol Chem. 1998;273:26977–81.

    Article  PubMed  CAS  Google Scholar 

  68. Badea T, Niculescu F, Soane L, Fosbrink M, Sorana H, Rus V, Shin ML, Rus H. RGC-32 increases p34CDC2 kinase activity and entry of aortic smooth muscle cells into S-phase. J Biol Chem. 2002;277:502–8.

    Article  PubMed  CAS  Google Scholar 

  69. Fosbrink M, Cudrici C, Tegla CA, Soloviova K, Ito T, Vlaicu S, Rus V, Niculescu F, Rus H. Response gene to complement 32 is required for C5b-9 induced cell cycle activation in endothelial cells. Exp Mol Pathol. 2009;86:87–94.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med. 2012;2:a011056.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  71. Spinas E, Kritas SK, Saggini A, Mobili A, Caraffa A, Antinolfi P, Pantalone A, Tei M, Speziali A, Saggini R, Conti P. Role of mast cells in atherosclerosis: a classical inflammatory disease. Int J Immunopathol Pharmacol. 2014;27:517–21.

    PubMed  CAS  Google Scholar 

  72. Lv YB, Jing J, Li JM, Zhong JP, Fang L, Yang B. Assessment of RANTES levels as the indicators of plaque vulnerability in rabbit models of atherosclerosis. Pathol Res Pract. 2014;210:1031–7.

    Article  PubMed  CAS  Google Scholar 

  73. An X, Jin Y, Guo H, Foo SY, Cully BL, Wu J, Zeng H, Rosenzweig A, Li J. Response gene to complement 32, a novel hypoxia-regulated angiogenic inhibitor. Circulation. 2009;120:617–27.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. Cui XB, Guo X, Chen SY. Response gene to complement 32 deficiency causes impaired placental angiogenesis in mice. Cardiovasc Res. 2013;99:632–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Wang JN, Shi N, Xie WB, Guo X, Chen SY. Response gene to complement 32 promotes vascular lesion formation through stimulation of smooth muscle cell proliferation and migration. Arterioscler Thromb Vasc Biol. 2011;31:e19–26.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  76. Tegla CA, Cudrici CD, Azimzadeh P, Singh AK, Trippe R 3rd, Khan A, Chen H, Andrian-Albescu M, Royal W 3rd, Bever C, Rus V, Rus H. Dual role of response gene to complement-32 in multiple sclerosis. Exp Mol Pathol. 2013;94:17–28.

    Article  PubMed  CAS  Google Scholar 

  77. Zhao P, Gao D, Wang Q, Song B, Shao Q, Sun J, Ji C, Li X, Li P, Qu X. Response gene to complement 32 (RGC-32) expression on M2-polarized and tumor-associated macrophages is M-CSF-dependent and enhanced by tumor-derived IL-4. Cell Mol Immunol. 2014. doi:10.1038/cmi.2014.108.

    Google Scholar 

  78. Tang R, Zhang G, Chen SY. Response gene to complement 32 protein promotes macrophage phagocytosis via activation of protein kinase C pathway. J Biol Chem. 2014;289:22715–22.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  79. Colin S, Chinetti-Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis. Immunol Rev. 2014;262:153–66.

    Article  PubMed  CAS  Google Scholar 

  80. Vlaicu SI, Cudrici C, Ito T, Fosbrink M, Tegla CA, Rus V, Mircea PA, Rus H. Role of response gene to complement 32 in diseases. Arch Immunol Ther Exp. 2008;56:115–22 (Warsz).

    Article  CAS  Google Scholar 

  81. Schmiedt W, Kinscherf R, Deigner HP, Kamencic H, Nauen O, Kilo J, Oelert H, Metz J, Bhakdi S. Complement C6 deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 1998;18:1790–5.

    Article  PubMed  CAS  Google Scholar 

  82. 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;172:547–57.

    Article  PubMed  CAS  Google Scholar 

  83. Lewis RD, Jackson CL, Morgan BP, Hughes TR. The membrane attack complex of complement drives the progression of atherosclerosis in apolipoprotein E knockout mice. Mol Immunol. 2010;47:1098–105.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  84. An G, Miwa T, Song WL, Lawson JA, Rader DJ, Zhang Y, Song WC. CD59 but not DAF deficiency accelerates atherosclerosis in female ApoE knockout mice. Mol Immunol. 2009;46:1702–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Wu G, Hu W, Shahsafaei A, Song W, Dobarro M, Sukhova GK, Bronson RR, Shi GP, Rother RP, Halperin JA, Qin X. Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res. 2009;104:550–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  86. Liu F, Wu L, Wu G, Wang C, Zhang L, Tomlinson S, Qin X. Targeted mouse complement inhibitor CR2-Crry protects against the development of atherosclerosis in mice. Atherosclerosis. 2014;234:237–43.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  87. Hamada N, Miyata M, Eto H, Ikeda Y, Shirasawa T, Akasaki Y, Miyauchi T, Furusho Y, Nagaki A, Aronow BJ, Tei C. Loss of clusterin limits atherosclerosis in apolipoprotein E-deficient mice via reduced expression of Egr-1 and TNF-alpha. J Atheroscler Thromb. 2011;18:209–16.

    Article  PubMed  CAS  Google Scholar 

  88. Yun S, Leung VW, Botto M, Boyle JJ, Haskard DO. Brief report: accelerated atherosclerosis in low-density lipoprotein receptor-deficient mice lacking the membrane-bound complement regulator CD59. Arterioscler Thromb Vasc Biol. 2008;28:1714–6.

    Article  PubMed  CAS  Google Scholar 

  89. Patel S, Thelander EM, Hernandez M, Montenegro J, Hassing H, Burton C, Mundt S, Hermanowski-Vosatka A, Wright SD, Chao YS, Detmers PA. ApoE(−/−) mice develop atherosclerosis in the absence of complement component C5. Biochem Biophys Res Commun. 2001;286:164–70.

    Article  PubMed  CAS  Google Scholar 

  90. Shagdarsuren E, Bidzhekov K, Mause SF, Simsekyilmaz S, Polakowski T, Hawlisch H, Gessner JE, Zernecke A, Weber C. C5a receptor targeting in neointima formation after arterial injury in atherosclerosis-prone mice. Circulation. 2010;122:1026–36.

    Article  PubMed  CAS  Google Scholar 

  91. Manthey HD, Thomas AC, Shiels IA, Zernecke A, Woodruff TM, Rolfe B, Taylor SM. Complement C5a inhibition reduces atherosclerosis in ApoE−/− mice. Faseb J. 2011;25:2447–55.

    Article  PubMed  CAS  Google Scholar 

  92. Lu X, Xia M, Endresz V, Faludi I, Mundkur L, Gonczol E, Chen D, Kakkar VV. Immunization with a combination of 2 peptides derived from the C5a receptor significantly reduces early atherosclerotic lesion in Ldlr(tm1Her) Apob(tm2Sgy) J mice. Arterioscler Thromb Vasc Biol. 2012;32:2358–71.

    Article  PubMed  CAS  Google Scholar 

  93. Wezel A, de Vries MR, Lagraauw HM, Foks AC, Kuiper J, Quax PH, Bot I. Complement factor C5a induces atherosclerotic plaque disruptions. J Cell Mol Med. 2014;18:2020–30.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  94. Buono C, Come CE, Witztum JL, Maguire GF, Connelly PW, Carroll M, Lichtman AH. Influence of C3 deficiency on atherosclerosis. Circulation. 2002;105:3025–31.

    Article  PubMed  CAS  Google Scholar 

  95. Persson L, Boren J, Robertson AK, Wallenius V, Hansson GK, Pekna M. Lack of complement factor C3, but not factor B, increases hyperlipidemia and atherosclerosis in apolipoprotein E−/− low-density lipoprotein receptor−/− mice. Arterioscler Thromb Vasc Biol. 2004;24:1062–7.

    Article  PubMed  CAS  Google Scholar 

  96. Steiner T, Francescut L, Byrne S, Hughes T, Jayanthi A, Guschina I, Harwood J, Cianflone K, Stover C, Francis S. Protective role for properdin in progression of experimental murine atherosclerosis. PLoS One. 2014;9:e92404.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  97. Malik TH, Cortini A, Carassiti D, Boyle JJ, Haskard DO, Botto M. The alternative pathway is critical for pathogenic complement activation in endotoxin- and diet-induced atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation. 2010;122:1948–56.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  98. Leung VW, Yun S, Botto M, Mason JC, Malik TH, Song W, Paixao-Cavalcante D, Pickering MC, Boyle JJ, Haskard DO. Decay-accelerating factor suppresses complement C3 activation and retards atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol. 2009;175:1757–67.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Lewis RD, Perry MJ, Guschina IA, Jackson CL, Morgan BP, Hughes TR. CD55 deficiency protects against atherosclerosis in ApoE-deficient mice via C3a modulation of lipid metabolism. Am J Pathol. 2011;179:1601–7.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  100. Sakuma M, Morooka T, Wang Y, Shi C, Croce K, Gao H, Strainic M, Medof ME, Simon DI. The intrinsic complement regulator decay-accelerating factor modulates the biological response to vascular injury. Arterioscler Thromb Vasc Biol. 2010;30:1196–202.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  101. Bhatia VK, Yun S, Leung V, Grimsditch DC, Benson GM, Botto MB, Boyle JJ, Haskard DO. Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol. 2007;170:416–26.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  102. Shagdarsuren E, Bidzhekov K, Djalali-Talab Y, Liehn EA, Hristov M, Matthijsen RA, Buurman WA, Zernecke A, Weber C. C1-esterase inhibitor protects against neointima formation after arterial injury in atherosclerosis-prone mice. Circulation. 2008;117:70–8.

    Article  PubMed  CAS  Google Scholar 

  103. Granger CB, Mahaffey KW, Weaver WD, Theroux P, Hochman JS, Filloon TG, Rollins S, Todaro TG, Nicolau JC, Ruzyllo W, Armstrong PW. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation. 2003;108:1184–90.

    Article  PubMed  CAS  Google Scholar 

  104. Mahaffey KW, Granger CB, Nicolau JC, Ruzyllo W, Weaver WD, Theroux P, Hochman JS, Filloon TG, Mojcik CF, Todaro TG, Armstrong PW. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation. 2003;108:1176–83.

    Article  PubMed  CAS  Google Scholar 

  105. Verrier ED, Shernan SK, Taylor KM, Van de Werf F, Newman MF, Chen JC, Carrier M, Haverich A, Malloy KJ, Adams PX, Todaro TG, Mojcik CF, Rollins SA, Levy JH. Terminal complement blockade with pexelizumab during coronary artery bypass graft surgery requiring cardiopulmonary bypass: a randomized trial. JAMA. 2004;291:2319–27.

    Article  PubMed  CAS  Google Scholar 

  106. Shernan SK, Fitch JC, Nussmeier NA, Chen JC, Rollins SA, Mojcik CF, Malloy KJ, Todaro TG, Filloon T, Boyce SW, Gangahar DM, Goldberg M, Saidman LJ, Mangano DT. Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass. Ann Thorac Surg. 2004;77:942–9 discussion 949–950.

    Article  PubMed  Google Scholar 

  107. Mahaffey KW, Van de Werf F, Shernan SK, Granger CB, Verrier ED, Filloon TG, Todaro TG, Adams PX, Levy JH, Hasselblad V, Armstrong PW. Effect of pexelizumab on mortality in patients with acute myocardial infarction or undergoing coronary artery bypass surgery: a systematic overview. Am Heart J. 2006;152:291–6.

    Article  PubMed  CAS  Google Scholar 

  108. Armstrong PW, Granger CB, Adams PX, Hamm C, Holmes D Jr, O’Neill WW, Todaro TG, Vahanian A, Van de Werf F. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA. 2007;297:43–51.

    Article  PubMed  CAS  Google Scholar 

  109. Smith PK, Shernan SK, Chen JC, Carrier M, Verrier ED, Adams PX, Todaro TG, Muhlbaier LH, Levy JH. Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials. J Thorac Cardiovasc Surg. 2011;142:89–98.

    Article  PubMed  CAS  Google Scholar 

  110. Martel C, Granger CB, Ghitescu M, Stebbins A, Fortier A, Armstrong PW, Bonnefoy A, Theroux P. Pexelizumab fails to inhibit assembly of the terminal complement complex in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Insight from a substudy of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Am Heart J. 2012;164:43–51.

    Article  PubMed  CAS  Google Scholar 

  111. Thielmann M, Marggraf G, Neuhauser M, Forkel J, Herold U, Kamler M, Massoudy P, Jakob H. Administration of C1-esterase inhibitor during emergency coronary artery bypass surgery in acute ST-elevation myocardial infarction. Eur J Cardiothorac Surg. 2006;30:285–93.

    Article  PubMed  Google Scholar 

  112. Fattouch K, Bianco G, Speziale G, Sampognaro R, Lavalle C, Guccione F, Dioguardi P, Ruvolo G. Beneficial effects of C1 esterase inhibitor in ST-elevation myocardial infarction in patients who underwent surgical reperfusion: a randomised double-blind study. Eur J Cardiothorac Surg. 2007;32:326–32.

    Article  PubMed  Google Scholar 

  113. Hollander W, Colombo MA, Kirkpatrick B, Paddock J. Soluble proteins in the human atherosclerotic plaque. With spectral reference to immunoglobulins, C3-complement component, alpha 1-antitrypsin and alpha 2-macroglobulin. Atherosclerosis. 1979;34:391–405.

    Article  PubMed  CAS  Google Scholar 

  114. Hansson GK, Holm J, Kral JG. Accumulation of IgG and complement factor C3 in human arterial endothelium and atherosclerotic lesions. Acta Pathol Microbiol Immunol Scand A. 1984;92:429–35.

    PubMed  CAS  Google Scholar 

  115. Seifert PS, Hugo F, Hansson GK, Bhakdi S. Prelesional complement activation in experimental atherosclerosis. Terminal C5b-9 complement deposition coincides with cholesterol accumulation in the aortic intima of hypercholesterolemic rabbits. Lab Investig. 1989;60:747–54.

    PubMed  CAS  Google Scholar 

  116. Niculescu F, Niculescu T, Rus H. C5b-9 terminal complement complex assembly on apoptotic cells in human arterial wall with atherosclerosis. Exp Mol Pathol. 2004;76:17–23.

    Article  PubMed  CAS  Google Scholar 

  117. Arlaud GJ, Biro A, Ling WL. Enzymatically modified low-density lipoprotein is recognized by c1q and activates the classical complement pathway. J Lipids. 2011;2011:376092.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  118. Fraser DA, Tenner AJ. Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages. J Immunol. 2010;185:3932–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  119. Spivia W, Magno PS, Le P, Fraser DA. Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins. Inflamm Res. 2014;63:885–93.

    Article  PubMed  CAS  Google Scholar 

  120. Hertle E, van Greevenbroek MM, Arts IC, van der Kallen CJ, Geijselaers SL, Feskens EJ, Jansen EH, Schalkwijk CG, Stehouwer CD. Distinct associations of complement C3a and its precursor C3 with atherosclerosis and cardiovascular disease. CODAM Study. Thromb Haemost. 2014;111:1102–11.

    Article  PubMed  CAS  Google Scholar 

  121. Carter AM, Prasad UK, Grant PJ. Complement C3 and C-reactive protein in male survivors of myocardial infarction. Atherosclerosis. 2009;203:538–43.

    Article  PubMed  CAS  Google Scholar 

  122. Muscari A, Bozzoli C, Puddu GM, Sangiorgi Z, Dormi A, Rovinetti C, Descovich GC, Puddu P. Association of serum C3 levels with the risk of myocardial infarction. Am J Med. 1995;98:357–64.

    Article  PubMed  CAS  Google Scholar 

  123. Akhtar N, Taher A, Rahman R, Chowdhury AK. Serum complements and heart fatty acid binding protein in Bangladeshi patients with acute myocardial infarction. Heart Asia. 2012;4:125–8.

    Article  Google Scholar 

  124. Iltumur K, Karabulut A, Toprak G, Toprak N. Complement activation in acute coronary syndromes. APMIS. 2005;113:167–74.

    Article  PubMed  CAS  Google Scholar 

  125. Distelmaier K, Adlbrecht C, Jakowitsch J, Winkler S, Dunkler D, Gerner C, Wagner O, Lang IM, Kubicek M. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost. 2009;102:564–72.

    PubMed  CAS  Google Scholar 

  126. Foreman KE, Vaporciyan AA, Bonish BK, Jones ML, Johnson KJ, Glovsky MM, Eddy SM, Ward PA. C5a-induced expression of P-selectin in endothelial cells. J Clin Investig. 1994;94:1147–55.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  127. Patzelt J, Mueller KA, Breuning S, Karathanos A, Schleicher R, Seizer P, Gawaz M, Langer HF, Geisler T. Expression of anaphylatoxin receptors on platelets in patients with coronary heart disease. Atherosclerosis. 2015;238:289–95.

    Article  PubMed  CAS  Google Scholar 

  128. An G, Ren G, An F, Zhang C. Role of C5a-C5aR axis in the development of atherosclerosis. Sci China Life Sci. 2014;57:790–4.

    Article  PubMed  CAS  Google Scholar 

  129. de Vries MR, Wezel A, Schepers A, van Santbrink PJ, Woodruff TM, Niessen HW, Hamming JF, Kuiper J, Bot I, Quax PH. Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease. Cardiovasc Res. 2013;97:311–20.

    Article  PubMed  CAS  Google Scholar 

  130. Speidl WS, Kastl SP, Hutter R, Katsaros KM, Kaun C, Bauriedel G, Maurer G, Huber K, Badimon JJ, Wojta J. The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro. Faseb J. 2011;25:35–44.

    Article  PubMed  CAS  Google Scholar 

  131. Speidl WS, Exner M, Amighi J, Kastl SP, Zorn G, Maurer G, Wagner O, Huber K, Minar E, Wojta J, Schillinger M. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Eur Heart J. 2005;26:2294–9.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Deborah McClellan for editing this manuscript. This work was supported in part by Veterans Administration Merit Awards BX001458 and IMMB-002-065 (both to H.R.). Dr. Sonia Vlaicu’s work was partially financed by POSDRU Grant No. 159/1.5/S/138776 with the title: “Model colaborativ institutional pentru translatarea cercetarii stiintifice biomedicale in practica clinica—TRANSCENT.”

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Authors and Affiliations

  1. Department of Neurology, School of Medicine Baltimore, University of Maryland, 655 W. Baltimore Street, Baltimore, MD, 21201, USA

    Sonia I. Vlaicu, Alexandru Tatomir, Armugam P. Mekala & Horea Rus

  2. Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Sonia I. Vlaicu & Petru A. Mircea

  3. Division of Rheumatology and Immunology, Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Violeta Rus & Florin Niculescu

  4. Research Service, Veterans Administration Maryland Health Care System, Baltimore, MD, USA

    Armugam P. Mekala & Horea Rus

  5. Veterans Administrdtion Multiple Sclerosis Center of Excellence, Baltimore, MD, USA

    Horea Rus

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  1. Sonia I. Vlaicu
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  2. Alexandru Tatomir
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Correspondence to Horea Rus.

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Vlaicu, S.I., Tatomir, A., Rus, V. et al. The role of complement activation in atherogenesis: the first 40 years. Immunol Res 64, 1–13 (2016). https://doi.org/10.1007/s12026-015-8669-6

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