Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Current Position on the Role of Monomeric C-reactive Protein in Vascular Pathology and Atherothrombosis

Author(s): Ivan S. Melnikov, Sergey G. Kozlov, Olga S. Saburova, Yulia N. Avtaeva, Lyudmila V. Prokofieva and Zufar A. Gabbasov*

Volume 26, Issue 1, 2020

Page: [37 - 43] Pages: 7

DOI: 10.2174/1381612825666191216144055

Price: $65

Abstract

C-reactive Protein (CRP) is an acute phase reactant, belonging to the pentraxin family of proteins. Its level rises up to 1000-fold in response to acute inflammation. High sensitivity CRP level is utilized as an independent biomarker of inflammation and cardiovascular disease. The accumulating data suggests that CRP has two distinct forms. It is predominantly produced in the liver in a native pentameric form (nCRP). At sites of local inflammation and tissue injury it may bind to phosphocholine-rich membranes of activated and apoptotic cells and their microparticles, undergoing irreversible dissociation to five monomeric subunits, termed monomeric CRP (mCRP). Through dissociation, CRP deposits into tissues and acquires distinct proinflammatory properties. It activates both classic and alternative complement pathways, binding complement component C1q and factor H. mCRP actively participates in the development of endothelial dysfunction. It activates leukocytes, inducing cytokine release and monocyte recruitment. It may also play a role in the polarization of monocytes and T cells into proinflammatory phenotypes. It may be involved in low-density lipoproteins (LDL) opsonization and uptake by macrophages. mCRP deposits were detected in samples of atherosclerotic lesions from human aorta, carotid, coronary and femoral arteries. mCRP may also induce platelet aggregation and thrombus formation, thus contributing in multiple ways in the development of atherosclerosis and atherothrombosis. In this mini-review, we will provide an insight into the process of conformational rearrangement of nCRP, leading to dissociation, and describe known effects of mCRP. We will provide a rationalization for mCRP involvement in the development of atherosclerosis and atherothrombosis.

Keywords: Monomeric C-reactive protein, modified C-reactive protein, inflammation, atherosclerosis, atherothrombosis, dissociation, complement.

« Previous Next »
[1]
Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1930; 52(4): 561-71.
[http://dx.doi.org/10.1084/jem.52.4.561] [PMID: 19869788]
[2]
Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107(3): 363-9.
[http://dx.doi.org/10.1161/01.CIR.0000053730.47739.3C] [PMID: 12551853]
[3]
Pearson TA, Mensah GA, Alexander RW, et al. Centers for disease control and prevention; American heart association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the American heart association. Circulation 2003; 107(3): 499-511.
[http://dx.doi.org/10.1161/01.CIR.0000052939.59093.45] [PMID: 12551878]
[4]
Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21): 2195-207.
[http://dx.doi.org/10.1056/NEJMoa0807646] [PMID: 18997196]
[5]
Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119-31.
[http://dx.doi.org/10.1056/NEJMoa1707914] [PMID: 28845751]
[6]
Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU. Targeting C-Reactive protein in inflammatory disease by preventing conformational changes. Mediators Inflamm 2015; 2015 372432
[http://dx.doi.org/10.1155/2015/372432] [PMID: 26089599]
[7]
Thiele JR, Habersberger J, Braig D, et al. Dissociation of pentameric to monomeric C-reactive protein localizes and aggravates inflammation: in vivo proof of a powerful proinflammatory mechanism and a new anti-inflammatory strategy. Circulation 2014; 130(1): 35-50.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.007124] [PMID: 24982116]
[8]
Eisenhardt SU, Habersberger J, Murphy A. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques Circ Res 2009; Jul; 17. 105(2): 128-37.
[9]
Mold C, Gewurz H, Du Clos TW. Regulation of complement activation by C-reactive protein. Immunopharmacology 1999; 42(1-3): 23-30.
[http://dx.doi.org/10.1016/S0162-3109(99)00007-7] [PMID: 10408362]
[10]
Vilahur G, Badimon L. Biological actions of pentraxins. Vascul Pharmacol 2015; 73: 38-44.
[http://dx.doi.org/10.1016/j.vph.2015.05.001] [PMID: 25962566]
[11]
Devaraj S, Jialal I. C-reactive protein polarizes human macrophages to an M1 phenotype and inhibits transformation to the M2 phenotype. Arterioscler Thromb Vasc Biol 2011; 31(6): 1397-402.
[http://dx.doi.org/10.1161/ATVBAHA.111.225508] [PMID: 21415385]
[12]
Calabro P, Chang DW, Willerson JT, Yeh ETH. Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. J Am Coll Cardiol 2005; 46(6): 1112-3.
[http://dx.doi.org/10.1016/j.jacc.2005.06.017] [PMID: 16168299]
[13]
Kolb-Bachofen V, Puchta-Teudt N, Egenhofer C. Expression of membrane-associated C-reactive protein by human monocytes: indications for a selectin-like activity participating in adhesion. Glycoconj J 1995; 12(2): 122-7.
[http://dx.doi.org/10.1007/BF00731355] [PMID: 7620328]
[14]
Ciubotaru I, Potempa LA, Wander RC. Production of modified C-reactive protein in U937-derived macrophages. Exp Biol Med (Maywood) 2005; 230(10): 762-70.
[http://dx.doi.org/10.1177/153537020523001010] [PMID: 16246904]
[15]
Dong Q, Wright JR. Expression of C-reactive protein by alveolar macrophages. J Immunol 1996; 156(12): 4815-20.
[PMID: 8648129]
[16]
Shrive AK, Cheetham GM, Holden D, et al. Three dimensional structure of human C-reactive protein. Nat Struct Biol 1996; 3(4): 346-54.
[http://dx.doi.org/10.1038/nsb0496-346] [PMID: 8599761]
[17]
Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure 1999; 7(2): 169-77.
[http://dx.doi.org/10.1016/S0969-2126(99)80023-9] [PMID: 10368284]
[18]
Hack CE, Wolbink GJ, Schalkwijk C, Speijer H, Hermens WT, van den Bosch H. A role for secretory phospholipase A2 and C-reactive protein in the removal of injured cells. Immunol Today 1997; 18(3): 111-5.
[http://dx.doi.org/10.1016/S0167-5699(97)01002-5] [PMID: 9078682]
[19]
Eisenhardt SU, Schmidt Y, Karaxha G, et al. Monitoring molecular changes induced by ischemia/reperfusion in human free muscle flap tissue samples. Ann Plast Surg 2012; 68(2): 202-8.
[http://dx.doi.org/10.1097/SAP.0b013e3181f77ba5] [PMID: 21508818]
[20]
Jiang HX, Siegel JN, Gewurz H. Binding and complement activation by C-reactive protein via the collagen-like region of C1q and inhibition of these reactions by monoclonal antibodies to C-reactive protein and C1q. J Immunol 1991; 146(7): 2324-30.
[PMID: 2005402]
[21]
Ji SR, 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(1): 284-94.
[http://dx.doi.org/10.1096/fj.06-6722com] [PMID: 17116742]
[22]
Taskinen S, Kovanen PT, Jarva H, Meri S, Pentikäinen MO. Binding of C-reactive protein to modified low-density-lipoprotein particles: identification of cholesterol as a novel ligand for C-reactive protein. Biochem J 2002; 367(Pt. 2): 403-12.
[http://dx.doi.org/10.1042/bj20020492] [PMID: 12102655]
[23]
Ji SR, Ma L, Bai CJ, et al. Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft microdomains. FASEB J 2009; 23(6): 1806-16.
[http://dx.doi.org/10.1096/fj.08-116962] [PMID: 19136614]
[24]
Li HY, Wang J, Wu YX, et al. Topological localization of monomeric C-reactive protein determines proinflammatory endothelial cell responses. J Biol Chem 2014; 289(20): 14283-90.
[http://dx.doi.org/10.1074/jbc.M114.555318] [PMID: 24711458]
[25]
Agrawal A, Shrive AK, Greenhough TJ, Volanakis JE. Topology and structure of the C1q-binding site on C-reactive protein. J Immunol 2001; 166(6): 3998-4004.
[http://dx.doi.org/10.4049/jimmunol.166.6.3998] [PMID: 11238646]
[26]
Ji SR, Wu Y, Potempa LA, Liang YH, Zhao J. 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(4): 935-41.
[http://dx.doi.org/10.1161/01.ATV.0000206211.21895.73] [PMID: 16456095]
[27]
Hage FG, Oparil S, Xing D, Chen YF, McCrory MA, Szalai AJ. C-reactive protein-mediated vascular injury requires complement. Arterioscler Thromb Vasc Biol 2010; 30(6): 1189-95.
[http://dx.doi.org/10.1161/ATVBAHA.110.205377] [PMID: 20339115]
[28]
Molins B, Fuentes-Prior P, Adán A, et al. Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants. Sci Rep 2016; 6: 22889.
[http://dx.doi.org/10.1038/srep22889] [PMID: 26961257]
[29]
Khreiss T, József L, Hossain S, Chan JS, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J Biol Chem 2002; 277(43): 40775-81.
[http://dx.doi.org/10.1074/jbc.M205378200] [PMID: 12198121]
[30]
Boras E, Slevin M, Alexander MY, et al. Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signalling pathway. Cytokine 2014; 69(2): 165-79.
[http://dx.doi.org/10.1016/j.cyto.2014.05.027] [PMID: 24972386]
[31]
Krupinski J, Turu MM, Martinez-Gonzalez J, et al. Endogenous expression of C-reactive protein is increased in active (ulcerated noncomplicated) human carotid artery plaques. Stroke 2006; 37(5): 1200-4.
[http://dx.doi.org/10.1161/01.STR.0000217386.37107.be] [PMID: 16601222]
[32]
Chirco KR, Whitmore SS, Wang K, et al. Monomeric C-reactive protein and inflammation in age-related macular degeneration. J Pathol 2016; 240(2): 173-83.
[http://dx.doi.org/10.1002/path.4766] [PMID: 27376713]
[33]
Slevin M, Matou S, Zeinolabediny Y, et al. Monomeric C-reactive protein--a key molecule driving development of Alzheimer’s disease associated with brain ischaemia? Sci Rep 2015; 5: 13281.
[http://dx.doi.org/10.1038/srep13281] [PMID: 26335098]
[34]
Strang F, Scheichl A, Chen YC, 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(3): 337-46.
[http://dx.doi.org/10.1111/j.1750-3639.2011.00539.x] [PMID: 21951392]
[35]
Schwedler SB, Guderian F, Dämmrich J, Potempa LA, Wanner C. Tubular staining of modified C-reactive protein in diabetic chronic kidney disease. Nephrol Dial Transplant 2003; 18(11): 2300-7.
[http://dx.doi.org/10.1093/ndt/gfg407] [PMID: 14551357]
[36]
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(1): 151-65.
[http://dx.doi.org/10.1111/j.1750-3639.2008.00256.x] [PMID: 19170684]
[37]
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(1): 64-72.
[http://dx.doi.org/10.1093/cvr/cvs237] [PMID: 22798388]
[38]
Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000; 1(1): 31-9.
[http://dx.doi.org/10.1038/35036052] [PMID: 11413487]
[39]
Khreiss T, József L, Potempa LA, Filep JG. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation 2004; 109(16): 2016-22.
[http://dx.doi.org/10.1161/01.CIR.0000125527.41598.68] [PMID: 15051635]
[40]
Ahrens I, Domeij H, Eisenhardt SU, et al. Opposing effects of monomeric and pentameric C-reactive protein on endothelial progenitor cells. Basic Res Cardiol 2011; 106(5): 879-95.
[http://dx.doi.org/10.1007/s00395-011-0191-y] [PMID: 21562922]
[41]
Maksimowicz-McKinnon K, Selzer F, Manzi S, et al. Poor 1-year outcomes after percutaneous coronary interventions in systemic lupus erythematosus: report from the National Heart, Lung, and Blood Institute Dynamic Registry. Circ Cardiovasc Interv 2008; 1(3): 201-8.
[http://dx.doi.org/10.1161/CIRCINTERVENTIONS.108.788745] [PMID: 20031679]
[42]
Turu MM, Slevin M, Matou S, et al. C-reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression. BMC Cell Biol 2008; 9: 47.
[http://dx.doi.org/10.1186/1471-2121-9-47] [PMID: 18764931]
[43]
Battegay EJ, Rupp J, Iruela-Arispe L, Sage EH, Pech M. PDGF-BB modulates endothelial proliferation and angiogenesis in vitro via PDGF beta-receptors. J Cell Biol 1994; 125(4): 917-28.
[http://dx.doi.org/10.1083/jcb.125.4.917] [PMID: 7514607]
[44]
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(10): 1452-9.
[http://dx.doi.org/10.1161/01.RES.0000267745.03488.47] [PMID: 17446434]
[45]
Schneeweis C, Gräfe M, Bungenstock A, Spencer-Hänsch C, Fleck E, Goetze S. Chronic CRP-exposure inhibits VEGF-induced endothelial cell migration. J Atheroscler Thromb 2010; 17(2): 203-12.
[http://dx.doi.org/10.5551/jat.3004] [PMID: 20173307]
[46]
Khreiss T, József L, Potempa LA, Filep JG. Loss of pentameric symmetry in C-reactive protein induces interleukin-8 secretion through peroxynitrite signaling in human neutrophils. Circ Res 2005; 97(7): 690-7.
[http://dx.doi.org/10.1161/01.RES.0000183881.11739.CB] [PMID: 16123332]
[47]
Gaul DS, Stein S, Matter CM. Neutrophils in cardiovascular disease. Eur Heart J 2017; 38(22): 1702-4.
[http://dx.doi.org/10.1093/eurheartj/ehx244] [PMID: 30052884]
[48]
Heuertz RM, Schneider GP, Potempa LA, Webster RO. Native and modified C-reactive protein bind different receptors on human neutrophils. Int J Biochem Cell Biol 2005; 37(2): 320-35.
[http://dx.doi.org/10.1016/j.biocel.2004.07.002] [PMID: 15474978]
[49]
Zouki C, Haas B, Chan JS, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion. J Immunol 2001; 167(9): 5355-61.
[http://dx.doi.org/10.4049/jimmunol.167.9.5355] [PMID: 11673552]
[50]
Roberts CA, Dickinson AK, Taams LS. The interplay between monocytes/macrophages and CD4(+) t cell subsets in rheumatoid arthritis. Front Immunol 2015; 6: 571.
[http://dx.doi.org/10.3389/fimmu.2015.00571] [PMID: 26635790]
[51]
Trial J, Potempa LA, Entman ML. The role of C-reactive protein in innate and acquired inflammation: new perspectives. Inflamm Cell Signal 2016; 3(2) e1409
[PMID: 27738646]
[52]
Fu T, Borensztajn J. Macrophage uptake of low-density lipoprotein bound to aggregated C-reactive protein: possible mechanism of foam-cell formation in atherosclerotic lesions. Biochem J 2002; 366(Pt. 1): 195-201.
[http://dx.doi.org/10.1042/bj20020045] [PMID: 12033985]
[53]
Taskinen S, Hyvönen M, Kovanen PT, Meri S, Pentikäinen MO. C-reactive protein binds to the 3beta-OH group of cholesterol in LDL particles. Biochem Biophys Res Commun 2005; 329(4): 1208-16.
[http://dx.doi.org/10.1016/j.bbrc.2005.02.091] [PMID: 15766555]
[54]
Ji SR, Wu Y, Potempa LA, Qiu Q, Zhao J. 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(4): 648-61.
[http://dx.doi.org/10.1016/j.biocel.2005.11.004] [PMID: 16376133]
[55]
Eisenhardt SU, Starke J, Thiele JR, et al. Pentameric CRP attenuates inflammatory effects of mmLDL by inhibiting mmLDL-monocyte interactions. Atherosclerosis 2012; 224(2): 384-93.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.07.039] [PMID: 22901456]
[56]
Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation 2001; 103(9): 1194-7.
[http://dx.doi.org/10.1161/01.CIR.103.9.1194] [PMID: 11238260]
[57]
Williams TN, Zhang CX, Game BA, He L, Huang Y. C-reactive protein stimulates MMP-1 expression in U937 histiocytes through Fc[gamma]RII and extracellular signal-regulated kinase pathway: an implication of CRP involvement in plaque destabilization. Arterioscler Thromb Vasc Biol 2004; 24(1): 61-6.
[http://dx.doi.org/10.1161/01.ATV.0000104014.24367.16] [PMID: 14592848]
[58]
Kobayashi S, Inoue N, Ohashi Y, et al. Interaction of oxidative stress and inflammatory response in coronary plaque instability: important role of C-reactive protein. Arterioscler Thromb Vasc Biol 2003; 23(8): 1398-404.
[http://dx.doi.org/10.1161/01.ATV.0000081637.36475.BC] [PMID: 12805076]
[59]
Vainas T, Stassen FR, de Graaf R, et al. C-reactive protein in peripheral arterial disease: relation to severity of the disease and to future cardiovascular events. J Vasc Surg 2005; 42(2): 243-51.
[http://dx.doi.org/10.1016/j.jvs.2005.03.060] [PMID: 16102622]
[60]
Sattler KJ, Woodrum JE, Galili O, et al. Concurrent treatment with renin-angiotensin system blockers and acetylsalicylic acid reduces nuclear factor kappaB activation and C-reactive protein expression in human carotid artery plaques. Stroke 2005; 36(1): 14-20.
[http://dx.doi.org/10.1161/01.STR.0000150643.08420.78] [PMID: 15576654]
[61]
Jabs WJ, 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(12): 1428-31.
[http://dx.doi.org/10.1161/01.CIR.0000092184.43176.91] [PMID: 12975260]
[62]
Molins B, Peña E, Vilahur G, Mendieta C, Slevin M, Badimon L. C-reactive protein isoforms differ in their effects on thrombus growth. Arterioscler Thromb Vasc Biol 2008; 28(12): 2239-46.
[http://dx.doi.org/10.1161/ATVBAHA.108.174359] [PMID: 18787187]
[63]
Wang J, Tang B, Liu X, et al. Increased monomeric CRP levels in acute myocardial infarction: a possible new and specific biomarker for diagnosis and severity assessment of disease. Atherosclerosis 2015; 239(2): 343-9.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.024] [PMID: 25682033]
[64]
Vilahur G, Hernández-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(3): 485-93.
[http://dx.doi.org/10.1111/j.1538-7836.2008.03244.x] [PMID: 19036073]
[65]
Molins B, Peña E, de la Torre R, Badimon L. Monomeric C-reactive protein is prothrombotic and dissociates from circulating pentameric C-reactive protein on adhered activated platelets under flow. Cardiovasc Res 2011; 92(2): 328-37.
[http://dx.doi.org/10.1093/cvr/cvr226] [PMID: 21859817]
[66]
Bisoendial RJ, Kastelein JJ, Levels JH, et al. Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res 2005; 96(7): 714-6.
[http://dx.doi.org/10.1161/01.RES.0000163015.67711.AB] [PMID: 15774855]
[67]
Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111(12): 1805-12.
[http://dx.doi.org/10.1172/JCI200318921] [PMID: 12813013]
[68]
Torzewski M, Waqar AB, Fan J. Animal models of C-reactive protein. Mediators Inflamm 2014; 2014 683598
[http://dx.doi.org/10.1155/2014/683598] [PMID: 24872599]
[69]
Taylor KE, Giddings JC, van den Berg CW. C-reactive protein-induced in vitro endothelial cell activation is an artefact caused by azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol 2005; 25(6): 1225-30.
[http://dx.doi.org/10.1161/01.ATV.0000164623.41250.28] [PMID: 15802626]
[70]
van den Berg CW, Taylor KE, Lang D. C-reactive protein-induced in vitro vasorelaxation is an artefact caused by the presence of sodium azide in commercial preparations. Arterioscler Thromb Vasc Biol 2004; 24(10): e168-71.
[http://dx.doi.org/10.1161/01.ATV.0000142807.92781.d9] [PMID: 15319265]
[71]
Danenberg HD, Kantak N, Grad E, Swaminathan RV, Lotan C, Edelman ER. C-reactive protein promotes monocyte-platelet aggregation: an additional link to the inflammatory-thrombotic intricacy. Eur J Haematol 2007; 78(3): 246-52.
[http://dx.doi.org/10.1111/j.1600-0609.2006.00808.x] [PMID: 17253971]

Rights & Permissions Print Cite
Article Metrics
34
6
World Health Day
© 2024 Bentham Science Publishers | Privacy Policy