Skip to main content
SpringerLink
Log in

Evidence for C-Reactive Protein's Role in (CRP) Vascular Disease: Atherothrombosis, Immuno-Regulation and CRP

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

For clinicians plasma C-reactive protein (CRP) levels are the only widely available tests that provide a tangible link between inflammation and atherosclerosis. New AHA/CDC joint guidelines from 2002–03 now include the measurement of CRP as a class IIa recommendation for stratifying patients with known cardiovascular disease (CVD) at a moderate (10–20%) 10-year event risk and a class IIb recommendation for patients without known CVD [1]. While the association of CRP and atherosclerosis is by now accepted, the molecular biology behind the association is evolving rapidly into a fascinating story. While some of the story remains obscure, this review aims to bridge the clinical and basic science and identify what is known about the role of this ancient molecule in atherosclerosis. The review covers CRP's interaction with atherosclerosis' major ingredients and cell types including the endothelium, monocytes and neutrophils, lipoproteins and the complement system. Taken together, the clinical and basic science leave the tantalizing impression that CRP has a fundamental role in atherogenesis, and hint at a more complex immunomodulatory effect which transforms the acute inflammatory response to vascular injury into the chronic inflammation seen in atherosclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. 1. Pearson T, Mensah G, Alexander R, et al. Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control an the American Heart Association. Circulation 2003;107:499–511.

    Google Scholar 

  2. Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. New England Journal of Medicine 1994;331(7):417–424.

    Google Scholar 

  3. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New England Journal of Medicine 1997;336(14):973–979.

    Google Scholar 

  4. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias: Inflammatory mechanisms and persistence of atrial fibrillation. Circulation 2001;104:2886–2891.

    Google Scholar 

  5. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome and the risk of incident cardiovascular events: An 8-year follow-up of 14,719 initially healthy women. Circulation 2003;107:391–397.

    Google Scholar 

  6. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99(7):855–860.

    Google Scholar 

  7. Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349(17):1595–1604.

    Google Scholar 

  8. de Filippi C, Wasserman S, Rosanio S, et al. Cardiac troponin T and C-reactive protein for predicting prognosis coronary atherosclerosis and cardiomyopathy in patients undergoing long-term hemodialysis. Journal of the American Medical Association 2003;290:353–359.

    Google Scholar 

  9. Eisenberg MS, Chen HJ, Warshofsky MK, et al. Elevated levels of plasma C-reactive protein are associated with decreased graft survival in cardiac transplant recipients. Circulation 2000;102(17):2100–2104.

    Google Scholar 

  10. Labarrere CA, Lee JB, Nelson DR, Al-Hassani M, Miller SJ, Pitts DE. C-reactive protein, arterial endothelial activation, and development of transplant coronary artery disease: A prospective study. Lancet 2002;360(9344):1462–1467.

    Google Scholar 

  11. Iwaki D, Osaki T, Mizunoe Y, Wai SN, Iwanaga S, Kawabata SI. Functional and structural diversities of Creactive proteins present in horseshoe crab hemolymph plasma. European Journal of Biochemistry 1999;264:314–326.

    Google Scholar 

  12. Bickerstaff MCM, Botto M, Hutchinson WL, et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nature Medicine 1999;5(6):694–697.

    Google Scholar 

  13. Clos TWD. C-reactive protein as a regulator of autoimmunity and inflammation. Arthritis and Rheumatism 2003;48(6):1475–1477.

    Google Scholar 

  14. Agrawal A, Cha-Molstad H, Samols D, Kushner I. Transactivation of C-reactive protein by IL-6 requires synergistic interaction of CCAAT/Enhancer binding protein b (C/EBPb) and Rel p501. Journal of Immunology 2001;166:2378–2384.

    Google Scholar 

  15. Ochrietor JD, Harrison KA, Zahedi K, Mortensen RF. Role of STAT3 and C/EBP in cytokine dependent expression of mouse serum amyloid P-component and C-reactive protein genes. Cytokine 2000;12(7):888–899

    Google Scholar 

  16. Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. American Journal of Pathology 2001;158(3):1039–1051.

    Google Scholar 

  17. Bacon PA, Stevens RJ, Carruthers DM, Young SP, Kitas GD. Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmunity Reviews 2002;1(6):338–347.

    Google Scholar 

  18. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. Journal of Clinical Investigation 1987;79(1):170–174.

    Google Scholar 

  19. Ikonomidis I, Andreotti F, Economou E, Stefanadis C, Toutouzas P, Nihoyannopoulos P. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation 1999;100:793–798.

    Google Scholar 

  20. Venugopal KS, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 2002;106:1439–1441.

    Google Scholar 

  21. Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connell JM. Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular disease. Clinical Science 2000;98(5):531–535.

    Google Scholar 

  22. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002;106:913–919.

    Google Scholar 

  23. Pasceri V, Willerson JT, Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165–2168.

    Google Scholar 

  24. Woollard KJ, Phillips DC, Griffiths HR. Direct modulatory effect of C-reactive protein on primary human monocyte adhesion to human endothelial cells. Clinical Experimental Immunology 2002;130:256–262.

    Google Scholar 

  25. Devaraj S, Xu DY, Jailal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: Implications for the metabolic syndrome and atherothrombosis. Circulation 2003;107(3):398–404.

    Google Scholar 

  26. Gosling J, Slaymaker S, Gu L, et al. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. Journal of Clinical Investigation 1999;103(6):773–778.

    Google Scholar 

  27. Guo J, Van Eck M, Twisk J, et al. Transplantation of monocyte CC-chemokine receptor 2-deficient bone marrow into 104 Mazer and Rabbani ApoE3-leiden mice inhibits atherogenesis. Arteriosclerosis, Thrombosis and Vascular Biology 2003;23:447–453.

    Google Scholar 

  28. Pasceri V, J. C, Willerson JT, Yeh ETH. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation 2001;103:2531–2534.

    Google Scholar 

  29. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–1772.

    Google Scholar 

  30. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Journal of Medicine 2000;342:836–843.

    Google Scholar 

  31. Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R. Interleukin-6 exacerbates early atherosclerosis in mice. Arteriosclerosis, Thrombosis and Vascular Biology 1999;19:2364–2367.

    Google Scholar 

  32. Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 2002;105:1890–1896.

    Google Scholar 

  33. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arteriosclerosis, Thrombosis and Vascular Biology 2000;20:2094–2099.

    Google Scholar 

  34. Zhong W, Zen Q, Tebo J, S chlottmann K, Coggeshall M, Mortensen RF. Effect of human C-reactive protein on chemokine and chemotactic factor-induced neutrophil chemotaxis and signaling. Journal of Immunology 1998;161:2533–2540.

    Google Scholar 

  35. Mold C, Gresham HD, Clos TWD. Serum amyloid P component and C-reactive protein mediate phagocytosis through murine Fc-gamma Rs. Journal of Immunology 2001;166:1200–1205.

    Google Scholar 

  36. Cabana VG, Gewrz H, Siegel JN. Interaction of very low density lipoproteins with rabbit C-reactive protein. Journal of Immunology 1982;128(5):2342–2348.

    Google Scholar 

  37. de Beer FC, Soutar AK, Baltz ML, Trayner IM, Feinstein A, Pepys MB. Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein. Journal of Experimental Medicine 1982;156:230–242.

    Google Scholar 

  38. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: Implications for atherosclerosis. Circulation 2001;103:1194–1197.

    Google Scholar 

  39. Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513–520.

    Google Scholar 

  40. Nakagomi A, Freedman SB, Geczy CL. Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: Relationship with age, sex, and hormone replacement treatment. Circulation 2000;101:1785–1791.

    Google Scholar 

  41. Wang C-H, Li S-H, Weisel RD, et al. C-reactive protein upregulates angiotensin type-1 receptors in vascular smooth muscle. Circulation 2003;107:1783–1790.

    Google Scholar 

  42. Hattori Y, Matsumura M, Kasai K. Vascular smooth cell activation by C-reactive protein. Cardiovascular Research 2003;58:186–195.

    Google Scholar 

  43. Calabro P, Willerson JT, Yeh ETH. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation 2003;108:1930–1932.

    Google Scholar 

  44. Bhakdi S, Torewski M, Klouche M, Hemmes M. Complement and atherogenesis: Binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arteriosclerosis, Thrombosis and Vascular Biology 1999;19:2348–2354.

    Google Scholar 

  45. Taskinen S, Kovanen PT, Jarva H, Meri S, Pentikainen MO. Binding of C-reactive protein to modified low-densitylipoprotein particles: Identification of cholesterol as a novel ligand for C-reative protein. Biochemistr Journal 2002;367:403–412.

    Google Scholar 

  46. Hansson GK, Holm J, Kral IG. Accumulation of IgG and complement factor C3 in human arterial endothelium and atherosclerotic lesions. Acta Pathologica, Microbiologica, et Immunologica Scandinavica 1984;92(6):429–435.

    Google Scholar 

  47. 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. Arteriosclerosis, Thrombosis and Vascular Biology 1998;18(9):1386–1392.

    Google Scholar 

  48. Agrawal A, Shrive AK, Greenhough TJ, Volanakis JE. Topology and structure of the C1q-binding site on Creactive protein. Journal of Immunology 2001;166:3998–4004.

    Google Scholar 

  49. Klegeris A, Singh EA, McGeer PL. Effects of C-reactive protein and pentosan polysulphate on human complement activation. Immunology 2002;106:381–388.

    Google Scholar 

  50. Jarva H, Joiranta TS, Hellwage J, P.F. Z, Seppo M. Regulation of complement activation by C-reactive protein: targeting the complement inhibitory activity of factor H by an interaction with short consensus repeat domains 7 and 8-111. Journal of Immunology 1999;163:3957–3962.

    Google Scholar 

  51. Suankratay CS, Mold C, Zhang Y, Potempa LA, Lint TF, Gewurz H. Complement regulation in innate immunity and the acute-phase response: Inihibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein. Clinical Experimental Immunology 1998;113(3):353–359.

    Google Scholar 

  52. Muller H, Fehr J. Binding of C-reactive protein to human polymorphonuclear leukocytes: Evidence for association of binding sites with Fc receptors. Journal of Immunology 1986;136(6):2202–2207.

    Google Scholar 

  53. Dobrinich R, Spagnuolo PJ. Binding of C-reactive protein to human neutrophils. Inhibition of respiratory burst activity}. Arthritis and Rheumatism 1991;34(8):1031–1038.

    Google Scholar 

  54. Buchta R, Gennaro R, Pontet M, Fridkin M, Romeo D. C-reactive protein decreases protein phosphorylation in stimulated human neutrophils. FEBS Letters 1988;237:173–177

    Google Scholar 

  55. Buchta R, Fridkin M, Pontet M, Contessi E, Scaggiante B, Romeo D. Modulation of human neutrophil function by C-reactive protein. European Journal of Biochemistry 1987;163(1).

  56. Roque M, Fallon JT, Badimon JJ, Zhang WX, Taubman MB, Reis ED. Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arteriosclerosis, Thrombosis and Vascular Biology 2000;20(2):335–342.

    Google Scholar 

  57. Bharadwaj D, Stein M-P, Volzer M, Mold C, Clos TWD. The major receptor for C-reactive protein on leukocytes is Evidence for C-Reactive Protein's Role in (CRP) Vascular Disease 105 Fc gamma receptor II. Journal of Experimental Medicine 1999;190(4):585–590.

    Google Scholar 

  58. Bodman-Smith KB, Melendez AJ, Campbell I, Harrison PT, Allen JM, Raynes JG. C-reactive protein-mediated phagocytosis and phospholipase D signalling through the high-affinity receptor for immunoglobulin G (Fc Gamma RI). Immunology 2002;107:252–260.

    Google Scholar 

  59. Stein MP, Mold C, Clos TWD. C-reactive protein binding to murine leukocytes requires Fc gamma receptors. Journal of Immunology 2000;164:1514–1520.

    Google Scholar 

  60. Xia D, Samols D. Transgenic mice expressing rabbit Creactive protein are resistant to endotoxemia. Proceedings of the National Academy of Sciences of the United States of America 1997;94(6):2575–2580.

    Google Scholar 

  61. Mold C, Rodriguez W, R odic-Polic B, Clos TWD. Creactive protein mediates protection from lipopolysaccharide through interactions with Fc gamma R. Journal of Immunology 2002;169:7019–7025.

    Google Scholar 

  62. Tilg H, Vannier E, Vachino G, Dinarello CA, Mier JW. Antiinflammatory properties of hepatic acute phase proteins: Preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells. Journal of Experimental Medicine 1993;178:1629–1636.

    Google Scholar 

  63. Gershov D, Kim SJ, Brot NE, K.B. C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an anti-inflammatory innate immune response: Implications for systemic auto-immunity. Journal of Experimental Medicine 2000;192:1353–1364.

    Google Scholar 

  64. Ridker PM, Rifai N, Clearfield M, et al. Measurement of Creactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. New England Journal of Medicine 2001;344:1959–1965.

    Google Scholar 

  65. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels. Journal of the American Medical Association 2001;286:64–75.

    Google Scholar 

  66. Ridker PM, Rifai N, Pfeffer M, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–235.

    Google Scholar 

  67. Balk EM, Lau J, Goudas LC, et al. Effects of statins on nonlipid serum markers associated with cardiovascular disease: A systematic review. Annals of Internal Medicine 2003;139(8):670–682.

    Google Scholar 

  68. Jenkins DJA, Kendall CWC, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. Journal of the American Medical Association 2003;290:502–510.

    Google Scholar 

  69. Jonkers IJ, Mohrschladt MF, Westendorp RG, van der Laarse A, Smelt AH. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: Reversal with bezafibrate therapy in a randomized controlled trial. American Journal of Medicine 2002; 112(4):274–280.

    Google Scholar 

  70. Kleemann R, Gervois PP, Verschuren L, S taels B, Princen HM, Kooistra T. Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation. Blood 2003;101(2):545–551.

    Google Scholar 

  71. Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET. Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation 2002;105:564–569.

    Google Scholar 

  72. Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC, Rimm EB. Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women. Circulation 2003;108(2):155–160.

    Google Scholar 

  73. Kennon S, Price C, Mills PG, et al. The effect of aspirin on C-reactive protein as a marker of risk in unstable angina. Journal of the American College of Cardiology 1999;37:1266–1277.

    Google Scholar 

  74. Cha JK, Jeong MH, Lee KM, et al. Changes in platelet p-selectin and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel. Journal of Thrombosis and Thrombolysis 2002;14(2):145–150.

    Google Scholar 

  75. Aggarwal A, Schneider DJ, Terrien EF, Terrien CM, Sobel BE, Dauerman HL. Comparison of effects of abciximab versus eptifibatide on C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist after coronary arterial stenting. American Journal of Cardiology 2003;91(11):1346–1349.

    Google Scholar 

  76. Lincoff AM, Kereiakes DJ, Mascelli MA, et al. Abciximab suppresses the rise in levels of circulating inflammatory markers after percutaneous coronary revascularization. Circulation 2001;104(2):163–167.

    Google Scholar 

  77. Lusis A. Atherosclerosis. Nature 2000;407:233–241.

    Google Scholar 

  78. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. Predictive value of C-reactive protein in patients with unstable angina pectoris undergoing coronary artery stent implantation. American Journal of Cardiology 2000;85:92–95.

    Google Scholar 

  79. Zee PYL, Ridker PM. Polymorphism in the human Creactive protein (CRP) gene, plasma concentrations ofCRP, and the risk of future arterial thrombosis. Atherosclerosis 2002;162:217–219.

    Google Scholar 

  80. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reative protein and the risk of developing peripheral vascular disease. Circulation 1998;97:425–428.

    Google Scholar 

  81. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemc stroke. Stroke 2001;32:917–924.

    Google Scholar 

  82. Schillinger M, Domanovitis H, Bayegan K, et al. C-reactive protein and mortality in patients with acute aortic disease. Intensive Care Medicine 2002;28:740–745.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA

    Sean P. Mazer, LeRoy E. Rabbani & LeRoy E. Rabbani

Authors
  1. Sean P. Mazer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. LeRoy E. Rabbani
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mazer, S.P., Rabbani, L.E. Evidence for C-Reactive Protein's Role in (CRP) Vascular Disease: Atherothrombosis, Immuno-Regulation and CRP. J Thromb Thrombolysis 17, 95–105 (2004). https://doi.org/10.1023/B:THRO.0000037664.77460.d8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:THRO.0000037664.77460.d8

Keywords

Search

Navigation