Abstract
C-reactive protein (CRP) is a prototypic human acute phase reactant composed of five identical subunits. Emerging evidence indicates that CRP is not merely a predictor of cardiovascular disease, but may also be a direct mediator. However, the diverse and sometimes contradictory activities of CRP have considerably hampered the attempts to define the exact role of CRP in atherogenesis. Here, we review the multiple layers of regulation of CRP’s structure and function, highlighting how local inflammation conditions, such as the abundance of damaged cell membranes and redox homeostasis, can tip the balance of the pro- and anti-inflammatory activities of CRP. We propose that the highly controlled interplay between different structural conformations of CRP underlies its intrinsic property as a fine modulator of inflammation and atherogenesis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Pepys M B, Hirschfield G M. C-reactive protein: A critical update. J Clin Invest, 2003, 111:1805–1812
Volanakis J E. Human C-reactive protein: Expression, structure, and function. Mol Immunol, 2001, 38:189–197
Bottazzi B, Doni A, Garlanda C, et al. An integrated view of humoral innate immunity: Pentraxins as a paradigm. Annu Rev Immunol, 2010, 28:157–183
Marnell L L, Mold C, Volzer M A, et al. C-reactive protein binds to Fc gamma RI in transfected COS cells. J Immunol, 1995, 155:2185–2193
Bharadwaj D, Stein M P, Volzer M, et al. The major receptor for C-reactive protein on leukocytes is fcgamma receptor II. J Exp Med, 1999, 190:585–590
Lu J, Marjon K D, Marnell L L, et al. Recognition and functional activation of the human IgA receptor (FcalphaRI) by C-reactive protein. Proc Natl Acad Sci USA, 2011, 108:4974–4979
Fujita Y, Kakino A, Harada-Shiba M, et al. C-reactive protein uptake by macrophage cell line via class-A scavenger receptor. Clin Chem, 2010, 56:478–481
Fujita Y, Kakino A, Nishimichi N, et al. Oxidized LDL receptor LOX-1 binds to C-reactive protein and mediates its vascular effects. Clin Chem, 2009, 55:285–294
Casas J P, Shah T, Hingorani A D, et al. C-reactive protein and coronary heart disease: A critical review. J Intern Med, 2008, 264:295–314
Reifenberg K, Lehr H A, Baskal D, et al. Role of C-reactive protein in atherogenesis: Can the apolipoprotein E knockout mouse provide the answer? Arterioscler Thromb Vasc Biol, 2005, 25: 1641–1646
Ridker P M, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med, 2002, 347:1557–1565
Danesh J, Wheeler J G, Hirschfield G M, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med, 2004, 350:1387–1397
Zacho J, Tybjaerg-Hansen A, Jensen J S, et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med, 2008, 359:1897–1908
Ridker P M, Danielson E, Fonseca F A, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med, 2008, 359:2195–2207
Nissen S E, Tuzcu E M, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med, 2005, 352:29–38
Torzewski J, Li K, Zimmermann O. Road map to drug discovery and development-inhibiting C-reactive protein for the treatment of cardiovascular disease. J Bioequiv Availab, 2011, S1:1–5
Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med, 1999, 340:115–126
Glass C K, Witztum J L. Atherosclerosis: The road ahead. Cell, 2001, 104:503–516
Ridker P M, Cannon C P, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med, 2005, 352:20–28
Reynolds G D, Vance R P. C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas. Arch Pathol Lab Med, 1987, 111:265–269
Zhang Y X, Cliff W J, Schoefl G I, et al. Coronary C-reactive protein distribution: Its relation to development of atherosclerosis. Atherosclerosis, 1999, 145:375–379
Chang M K, Binder C J, Torzewski M, et al. 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
Bhakdi S, Torzewski M, Paprotka K, et al. Possible protective role for C-reactive protein in atherogenesis: Complement activation by modified lipoproteins halts before detrimental terminal sequence. Circulation, 2004, 109:1870–1876
Torzewski J, Torzewski M, Bowyer D E, 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
Devaraj S, Singh U, Jialal I. The evolving role of C-reactive protein in atherothrombosis. Clin Chem, 2009, 55:229–238
Paul A, Yeh E T, Chan L. A proatherogenic role for C-reactive protein in vivo. Curr Opin Lipidol, 2005, 16:512–517
Pepys M B, Hirschfield G M, Tennent G A, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature, 2006, 440:1217–1221
Korngold E C, Januzzi J L Jr, Gantzer M L, et al. Amino-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein as predictors of sudden cardiac death among women. Circulation, 2009, 119:2868–2876
Khera A, de Lemos J A, Peshock R M, et al. Relationship between C-reactive protein and subclinical atherosclerosis: The Dallas Heart Study. Circulation, 2006, 113:38–43
Bos M J, Schipper C M, Koudstaal P J, et al. High serum C-reactive protein level is not an independent predictor for stroke: The Rotterdam Study. Circulation, 2006, 114:1591–1598
Paul A, Ko K W, Li L, et al. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice. Circulation, 2004, 109:647–655
Hirschfield G M, Gallimore J R, Kahan M C, et al. Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA, 2005, 102:8309–8314
Kovacs A, Tornvall P, Nilsson R, et al. Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. Proc Natl Acad Sci USA, 2007, 104:13768–13773
Teupser D, Weber O, Rao T N, et al. No reduction of atherosclerosis in C-reactive protein (CRP)-deficient mice. J Biol Chem, 2011, 286:6272–6279
Koike T, Kitajima S, Yu Y, et al. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation, 2009, 120:2088–2094
Verma S, Li S H, Badiwala M V, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation, 2002, 105:1890–1896
Verma S, Wang C H, Li S H, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation, 2002, 106:913–919
Clapp B R, Hirschfield G M, Storry C, et al. Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability. Circulation, 2005, 111:1530–1536
Taylor K E, Giddings J C, Van Den Berg C W. C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol, 2005, 25:1225–1230
Schwartz R, Osborne-Lawrence S, Hahner L, et al. C-reactive protein downregulates endothelial NO synthase and attenuates reendothelialization in vivo in mice. Circ Res, 2007, 100:1452–1459
Devaraj S, Du Clos T W, Jialal I. Binding and internalization of C-reactive protein by Fcgamma receptors on human aortic endothelial cells mediates biological effects. Arterioscler Thromb Vasc Biol, 2005, 25:1359–1363
Pepys M B, Gallimore J R, Lloyd J, et al. Isolation and characterization of pharmaceutical grade human pentraxins, serum amyloid P component and C-reactive protein, for clinical use. J Immunol Methods, 2012, 384:92–102
Singh U, Devaraj S, Dasu M R, et al. C-reactive protein decreases interleukin-10 secretion in activated human monocyte-derived macrophages via inhibition of cyclic AMP production. Arterioscler Thromb Vasc Biol, 2006, 26:2469–2475
Zhang R, Becnel L, Li M, et al. C-reactive protein impairs human CD14+ monocyte-derived dendritic cell differentiation, maturation and function. Eur J Immunol, 2006, 36:2993–3006
Van Vre E A, Bult H, Hoymans V Y, et al. Human C-reactive protein activates monocyte-derived dendritic cells and induces dendritic cell-mediated T-cell activation. Arterioscler Thromb Vasc Biol, 2008, 28:511–518
Pepys M B, Hawkins P N, Kahan M C, et al. Proinflammatory effects of bacterial recombinant human C-reactive protein are caused by contamination with bacterial products, not by C-reactive protein itself. Circ Res, 2005, 97:e97–103
Liu C, Wang S, Deb A, et al. Proapoptotic, antimigratory, antiproliferative, and antiangiogenic effects of commercial C-reactive protein on various human endothelial cell types in vitro: Implications of contaminating presence of sodium azide in commercial preparation. Circ Res, 2005, 97:135–143
Zhao J, Ji S R, Wu Y. C-reactive protein — A link between cardiovascular disease and inflammation. Acta Biophys Sin, 2010, 26:87–96
Schwedler S B, Filep J G, Galle J, et al. C-reactive protein: A family of proteins to regulate cardiovascular function. Am J Kidney Dis, 2006, 47:212–222
Singh S K, Suresh M V, Voleti B, et al. The connection between C-reactive protein and atherosclerosis. Ann Med, 2008, 40:110–120
Eisenhardt S U, Thiele J R, Bannasch H, et al. C-reactive protein: How conformational changes influence inflammatory properties. Cell Cycle, 2009, 8:3885–3892
Slevin M, Krupinski J. A role for monomeric C-reactive protein in regulation of angiogenesis, endothelial cell inflammation and thrombus formation in cardiovascular/cerebrovascular disease? Histol Histopathol, 2009, 24:1473–1478
Filep J G. Platelets affect the structure and function of C-reactive protein. Circ Res, 2009, 105:109–111
Potempa L A, Maldonado B A, Laurent P, et al. Antigenic, electrophoretic and binding alterations of human C-reactive protein modified selectively in the absence of calcium. Mol Immunol, 1983, 20:1165–1175
Wang M Y, Ji S R, Bai C J, et al. A redox switch in C-reactive protein modulates activation of endothelial cells. FASEB J, 2011, 25:3186–3196
Khreiss T, Jozsef L, Hossain S, et al. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J Biol Chem, 2002, 277:40775–40781
Kresl J J, Potempa L A, Anderson B E. Conversion of native oligomeric to a modified monomeric form of human C-reactive protein. Int J Biochem Cell Biol, 1998, 30:1415–1426
Motie M, Brockmeier S, Potempa L A. Binding of model soluble immune complexes to modified C-reactive protein. J Immunol, 1996, 156:4435–4441
Ji S R, Wu Y, Potempa L A, et al. Interactions of C-reactive protein with low-density lipoproteins: Implications for an active role of modified C-reactive protein in atherosclerosis. Int J Biochem Cell Biol, 2006, 38:648–661
Ji S R, Wu Y, Potempa L A, et al. Effect of modified C-reactive protein on complement activation: A possible complement regulatory role of modified or monomeric C-reactive protein in atherosclerotic lesions. Arterioscler Thromb Vasc Biol, 2006, 26:935–941
Singh S K, Suresh M V, Hammond D J Jr, et al. Binding of the monomeric form of C-reactive protein to enzymatically-modified low-density lipoprotein: Effects of phosphoethanolamine. Clin Chim Acta, 2009, 406:151–155
Biro A, Rovo Z, Papp D, et al. Studies on the interactions between C-reactive protein and complement proteins. Immunology, 2007, 121:40–50
Sjowal, C, Wettero J, Bengtsson T, et al. Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluidphase CRP-C1q interaction. Biochem Biophys Res Commun, 2007, 352:251–258
Mihlan M, Stippa S, Jozsi M, et al. Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H. Cell Death Differ, 2009, 16:1630–1640
Lauer N, Mihlan M, Hartmann A, et al. Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant. J Immunol, 2011, 187:4374–4383
Mihlan M, Blom A M, Kupreishvili K, et al. Monomeric C-reactive protein modulates classic complement activation on necrotic cells. FASEB J, 2011, 25:4198–4210
Yang X W, Tan Y, Yu F, et al. Interference of antimodified C-reactive protein autoantibodies from lupus nephritis in the biofunctions of modified C-reactive protein. Hum Immunol, 2012, 73:156–163
Rzychon M, Zegers I, Schimmel H. Analysis of the physicochemical state of C-reactive protein in different preparations including 2 certified reference materials. Clin Chem, 2010, 56:1475–1482
Wu Y, Ji S R, Wang H W, et al. Study of the spontaneous dissociation of rabbit C-reactive protein. Biochemistry (Mosc), 2002, 67:1377–1382
Potempa L A, Siegel J N, Fiedel B A, et al. Expression, detection and assay of a neoantigen (Neo-CRP) associated with a free, human C-reactive protein subunit. Mol Immunol, 1987, 24:531–541
Hakobyan S, Harris C L, Van Den Berg C W, et al. Complement factor H binds to denatured rather than to native pentameric C-reactive protein. J Biol Chem, 2008, 283:30451–30460
Wang H W, Sui S F. Dissociation and subunit rearrangement of membrane-bound human C-reactive proteins. Biochem Biophys Res Commun, 2001, 288:75–79
Ji S R, Wu Y, Zhu L, et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J, 2007, 21:284–294
Thompson D, Pepys M B, Wood S P. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure, 1999, 7:169–177
Gershov D, Kim S, Brot N, et al. C-Reactive protein binds to apop-totic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: Implications for systemic autoimmunity. J Exp Med, 2000, 192:1353–1364
Eisenhardt S U, Habersberger J, Murphy A, et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res, 2009, 105:128–137
Schwedler S B, Guderian F, Dammrich J, et al. Tubular staining of modified C-reactive protein in diabetic chronic kidney disease. Nephrol Dial Transplant, 2003, 18:2300–2307
Slevin M, Matou-Nasri S, Turu M, et al. Modified C-reactive protein is expressed by stroke neovessels and is a potent activator of angiogenesis in vitro. Brain Pathol, 2010, 20:151–165
Molins B, Pena E, De La Torre R, et al. Monomeric C-reactive protein is prothrombotic and dissociates from circulating pentameric C-reactive protein on adhered activated platelets under flow. Cardiovasc Res, 2011, 92:328–337
Strang F, Scheichl A, Chen Y C, et al. Amyloid plaques dissociate pentameric to monomeric C-reactive protein: A novel pathomechanism driving cortical inflammation in Alzheimer’s disease? Brain Pathol, 2012, 22:337–346
Habersberger J, Strang F, Scheichl A, et al. Circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction. Cardiovasc Res, 2012, 96:64–72
Wang M S, Messersmith R E, Reed S M. Membrane curvature recognition by C-reactive protein using lipoprotein mimics. Soft Matter, 2012, 8:3909–3918
Hammond D J Jr, Singh S K, Thompson J A, et al. Identification of acidic pH-dependent ligands of pentameric C-reactive protein. J Biol Chem, 2010, 285:36235–36244
Ciubotaru I, Potempa L A, Wander R C. Production of modified C-reactive protein in U937-derived macrophages. Exp Biol Med (Maywood), 2005, 230:762–770
Wang M S, Black J C, Knowles M K, et al. C-reactive protein (CRP) aptamer binds to monomeric but not pentameric form of CRP. Anal Bioanal Chem, 2011, 401:1309–1318
Tan Y, Yu F, Qu Z, et al. Modified C-reactive protein might be a target autoantigen of TINU syndrome. Clin J Am Soc Nephrol, 2011, 6:93–100
Wettero J, Nilsson L, Jonasson L, et al. Reduced serum levels of autoantibodies against monomeric C-reactive protein (CRP) in patients with acute coronary syndrome. Clin Chim Acta, 2009, 400:128–131
Sjowall C, Bengtsson A A, Sturfelt G, et al. Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus. Arthritis Res Ther, 2004, 6:R87–R94
Wettero J, Nilsson L, Jonasson L, et al. Reduced serum levels of autoantibodies against monomeric C-reactive protein (CRP) in patients with acute coronary syndrome. Clin Chim Acta, 2009, 400:128–131
Hoshino Y, Shioji K, Nakamura H, et al. From oxygen sensing to heart failure: Role of thioredoxin. Antioxid Redox Signal, 2007, 9:689–699
Yamawaki H, Haendeler J, Berk B C. Thioredoxin: A key regulator of cardiovascular homeostasis. Circ Res, 2003, 93:1029–1033
Ji S R, Ma L, Bai C J, et al. Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft microdomains. FASEB J, 2009, 23:1806–1816
Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol, 2000, 1:31–41
Li R, Ren M, Luo M, et al. Monomeric C-reactive protein alters fibrin clot properties on endothelial cells. Thromb Res, 2012, 129:e251–256
Vilahur G, Hernandez-Vera R, Molins B, et al. Short-term myocardial ischemia induces cardiac modified C-reactive protein expression and proinflammatory gene (cyclo-oxygenase-2, monocyte chemoattractant protein-1, and tissue factor) upregulation in peripheral blood mononuclear cells. J Thromb Haemost, 2009, 7:485–493
Patel D N, King C A, Bailey S R, et al. Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem, 2007, 282:27229–27238
Venugopal S K, Devaraj S, Jialal I. Macrophage conditioned medium induces the expression of C-reactive protein in human aortic endothelial cells: Potential for paracrine/autocrine effects. Am J Pathol, 2005, 166:1265–1271
Jabs W J, Theissing E, Nitschke M, et al. Local generation of C-reactive protein in diseased coronary artery venous bypass grafts and normal vascular tissue. Circulation, 2003, 108:1428–1431
Yasojima K, Schwab C, McGeer E G, et al. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol, 2001, 158:1039–1051
Nishihira K, Yamashita A, Imamura T, et al. Thioredoxin in coronary culprit lesions: Possible relationship to oxidative stress and intraplaque hemorrhage. Atherosclerosis, 2008, 201:360–367
Burke-Gaffney A, Callister M E, Nakamura H. Thioredoxin: Friend or foe in human disease? Trends Pharmacol Sci, 2005, 26:398–404
Watanabe R, Nakamura H, Masutani H, et al. Anti-oxidative, anti-cancer and anti-inflammatory actions by thioredoxin 1 and thioredoxin-binding protein-2. Pharmacol Ther, 2010, 127:261–270
El Kebir D, Zhang Y, Potempa L A, et al. C-reactive protein-derived peptide 201–206 inhibits neutrophil adhesion to endothelial cells and platelets through CD32. J Leukoc Biol, 2011, 90:1167–1175
Schwedler S B, Hansen-Hagge T, Reichert M, et al. Monomeric C-reactive protein decreases acetylated LDL uptake in human endothelial cells. Clin Chem, 2009, 55:1728–1731
Schwedler S B, Amann K, Wernicke K, et al. Native C-reactive protein (CRP) increases, whereas modified CRP reduces atherosclerosis in ApoE-knockout-mice. Circulation, 2005, 112:1016–1023
Kemp M, Go Y M, Jones D P. Nonequilibrium thermodynamics of thiol/disulfide redox systems: A perspective on redox systems biology. Free Radic Biol Med, 2008, 44:921–937
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is published with open access at Springerlink.com
Rights and permissions
This article is published under an open access license. Please check the 'Copyright Information' section either on this page or in the PDF for details of this license and what re-use is permitted. If your intended use exceeds what is permitted by the license or if you are unable to locate the licence and re-use information, please contact the Rights and Permissions team.
About this article
Cite this article
Ma, X., Ji, SR. & Wu, Y. Regulated conformation changes in C-reactive protein orchestrate its role in atherogenesis. Chin. Sci. Bull. 58, 1642–1649 (2013). https://doi.org/10.1007/s11434-012-5591-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11434-012-5591-3