C-Reactive Protein and Atherogenesis
2005; Elsevier BV; Volume: 167; Issue: 4 Linguagem: Inglês
10.1016/s0002-9440(10)61182-0
ISSN1525-2191
Autores Tópico(s)Lipid metabolism and disorders
ResumoIn this issue of The American Journal of Pathology, Sun and colleagues1Sun H Koike T Ichikawa T Hatakeyama K Shiomi M Zhang B Kitajima S Morimoto M Watanabe T Asada Y Chen YE Fan J C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.Am J Pathol. 2005; 167: 1139-1148Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar publish a potential key article in the field of C-reactive protein (CRP) and atherosclerosis, which is currently a lively topic in cardiovascular research. The reasons for this wide-reaching interest are briefly summarized as follows. First, CRP has been identified as a powerful cardiovascular risk marker.2Koenig W Sund M Fröhlich M Fischer HG Lowel H Doring A Hutchinson WL Pepys MB C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (monitoring of trends and determinants in cardiovascular disease) Augsburg Cohort Study, 1984 to 1992.Circulation. 1999; 99: 237-242Crossref PubMed Scopus (1769) Google Scholar, 3Ridker PM Hennekens CH Buring JE Rifai N C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.N Engl J Med. 2000; 342: 836-843Crossref PubMed Scopus (5011) Google Scholar Second, CRP may not only be a cardiovascular risk marker but also a risk factor, ie, CRP may be causally involved in atherogenesis.4Manolov DE Koenig W Hombach V Torzewski J C-reactive protein and atherosclerosis—is there a causal link?.Histol Histopathol. 2003; 18: 1189-1193PubMed Google Scholar, 5Jialal I Devaraj S Venugopal SK C-reactive protein: risk marker or mediator in atherothrombosis?.Hypertension. 2004; 44: 6-11Crossref PubMed Scopus (498) Google Scholar Third, if CRP is indeed a cardiovascular risk factor, the molecule may well be a target for drug development, and CRP inhibition might be a strategy for primary or secondary prevention of cardiovascular disease.6Ivashchenko Y Kramer F Schaefer S Bucher A Veit K Hombach V Busch A Ritzeler O Dedio J Torzewski J The protein kinase C-pathway is involved in C-reactive protein synthesis in human hepatocytes.Arterioscler Thromb Vasc Biol. 2005; 25: 1-7Google Scholar The medical and economical impact of these possibilities is evident. In analogy to other active areas in research, the role of CRP in cardiovascular disease is controversially discussed. Such controversial discussion relates to each of the three points raised above. The role of CRP as a cardiovascular risk marker is almost generally accepted, and evidence is based on several large and well-controlled trials.2Koenig W Sund M Fröhlich M Fischer HG Lowel H Doring A Hutchinson WL Pepys MB C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (monitoring of trends and determinants in cardiovascular disease) Augsburg Cohort Study, 1984 to 1992.Circulation. 1999; 99: 237-242Crossref PubMed Scopus (1769) Google Scholar, 3Ridker PM Hennekens CH Buring JE Rifai N C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.N Engl J Med. 2000; 342: 836-843Crossref PubMed Scopus (5011) Google Scholar The American Heart Association has already included CRP measurement into the guidelines for cardiovascular risk prediction.7Pearson TA Mensah GA Alexander RW Anderson JL Cannon RO Criqui M Fadl YY Fortmann SP Hong Y Myers GL Rifai N Smith Jr, SC Taubert K Tracy RP Vinicor F 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: 499-511Crossref PubMed Scopus (5130) Google Scholar Few populations, however, have shown less strong correlation of CRP plasma levels with cardiovascular events,8Danesh J Wheeler JG Hirschfield GM Eda S Eiriksdottir G Rumley A Lowe GD Pepys MB Gudnason V C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.N Engl J Med. 2004; 350: 1387-1397Crossref PubMed Scopus (2470) Google Scholar and consequently, some researchers doubt that CRP measurement adds useful information to the Framingham risk score. Concerning the second point, ie, the potential role of CRP as a cardiovascular risk factor, there is definitely no international consensus. CRP was first hypothesized to be involved in atherogenesis in 1982 when researchers demonstrated that CRP interacts with low-density lipoprotein (LDL),9de 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.J Exp Med. 1982; 156: 230-242Crossref PubMed Scopus (148) Google Scholar a finding that has recently been confirmed by others using various modified and nonmodified LDL molecules.10Bhakdi 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: 2348-2354Crossref PubMed Scopus (308) Google Scholar, 11Chang 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: 13043-13048Crossref PubMed Scopus (431) Google Scholar, 12Taskinen S Hyvonen M Kovanen PT Meri S Pentikainen MO C-reactive protein binds to the 3beta-OH group of cholesterol in LDL particles.Biochem Biophys Res Commun. 2005; 329: 1208-1216Crossref PubMed Scopus (34) Google Scholar Scientific interest waned, however, when the same group consecutively published that CRP is present neither in human nor in rabbit arterial lesions.13Rowe IF Walker LN Bowyer DE Soutar AK Smith LC Pepys MB Immunohistochemical studies of C-reactive protein and apolipoprotein B in inflammatory and arterial lesions.J Pathol. 1985; 145: 241-249Crossref PubMed Scopus (30) Google Scholar Two smaller publications on CRP deposition in human lesions were primarily ignored.14Reynolds GD Vance RP C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas.Arch Pathol Lab Med. 1987; 111: 265-269PubMed Google Scholar, 15Hatanaka K Li XA Masuda K Yutani C Yamamoto A Immunohistochemical localization of C-reactive protein-binding sites in human atherosclerotic aortic lesions by a modified streptavidin-biotin-staining method.Pathol Int. 1995; 45: 635-641Crossref PubMed Scopus (72) Google Scholar Interest returned with the results from epidemiology and the identification of CRP as a cardiovascular risk marker.2Koenig W Sund M Fröhlich M Fischer HG Lowel H Doring A Hutchinson WL Pepys MB C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (monitoring of trends and determinants in cardiovascular disease) Augsburg Cohort Study, 1984 to 1992.Circulation. 1999; 99: 237-242Crossref PubMed Scopus (1769) Google Scholar, 3Ridker PM Hennekens CH Buring JE Rifai N C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women.N Engl J Med. 2000; 342: 836-843Crossref PubMed Scopus (5011) Google Scholar In search for complement-activating molecules in human atherosclerotic lesions, it was demonstrated in 1998 that CRP is indeed ubiquitously present in all stages of human atherosclerosis and that it co-localizes with activated complement fragments.16Torzewski 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: 1386-1392Crossref PubMed Scopus (498) Google Scholar This finding also has been confirmed by several groups,17Yasojima K Schwab C McGeer EG McGeer PL Generation of C-reactive protein and complement components in atherosclerotic plaques.Am J Pathol. 2001; 158: 1039-1051Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar and since then various researchers have investigated a potential active contribution of CRP to atherosclerosis, suggesting that CRP activates monocytes/macrophages,18Torzewski M Rist C Mortensen RF Zwaka TP Bienek M Waltenberger J Koenig W Schmitz G Hombach V Torzewski J C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis.Arterioscler Thromb Vasc Biol. 2000; 20: 2094-2099Crossref PubMed Scopus (546) Google Scholar, 19Zwaka TP Hombach V Torzewski J C-reactive protein-mediated low density lipoprotein uptake by macrophages.Circulation. 2001; 103: 1194-1197Crossref PubMed Scopus (777) Google Scholar endothelial cells,20Pasceri V Willerson JT Yeh ET Direct proinflammatory effect of C-reactive protein on human endothelial cells.Circulation. 2000; 102: 2165-2168Crossref PubMed Scopus (1716) Google Scholar, 21Devaraj S Xu DY Jialal 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: 398-404Crossref PubMed Scopus (579) Google Scholar and vascular smooth muscle cells.22Wang CH Li SH Weisel RD Fedak PW Dumont AS Szmitko P Li RK Mickle DA Verma S C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle.Circulation. 2003; 107: 1783-1790Crossref PubMed Scopus (483) Google Scholar A critical point in all these studies is the use of commercially available CRP preparations that may contain contaminants such as lipopolysaccharide and azide. Indeed, it has recently been demonstrated that almost all of the published effects of CRP on endothelial cells are due to contamination of CRP preparations with azide and lipopolysaccharide.23Taylor 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: 1225-1230Crossref PubMed Scopus (146) Google Scholar, 24Liu C Wang S Deb A Nath KA Katusic ZS McConnell JP Caplice NM 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: 135-143Crossref PubMed Scopus (71) Google Scholar In this context it should be noted that CRP-mediated activation of endothelial cells and smooth muscle cells may not be biologically plausible and may lack a convincing molecular explanation. To understand a molecule's role in disease, the best approach might be to reconsider its role in physiology. CRP is an ancient immune molecule that shares many functional properties with antibodies: CRP binds to a variety of ligands (including LDL or modified LDL), activates complement,25Volanakis JE Complement activation by C-reactive protein complexes.Ann NY Acad Sci. 1982; 89: 235-250Crossref Scopus (227) Google Scholar opsonizes biological particles,26Mortensen RF Osmand AP Lint TF Gewurz H Interaction of C-reactive protein with lymphocytes and monocytes: complement-dependent adherence and phagocytosis.J Immunol. 1976; 117: 774-781PubMed Google Scholar and binds to and signals via Fcγ-receptors.27Bharadwaj D Stein MP Volzer M Mold C Du Clos TW The major receptor for C-reactive protein on leukocytes is fcgamma receptor II.J Exp Med. 1999; 190: 585-590Crossref PubMed Scopus (325) Google Scholar, 28Manolov DE Rocker C Hombach V Nienhaus GU Torzewski J Ultrasensitive confocal fluorescence microscopy of C-reactive protein interacting with FcgammaRIIa.Arterioscler Thromb Vasc Biol. 2004; 24: 2372-2377Crossref PubMed Scopus (44) Google Scholar CRP and complement appeared very early in the evolution of the immune system and so did monocytes/macrophages. It is thus likely that the target cell for CRP in vascular biology and atherosclerosis is the monocyte/macrophage and not the endothelial cell or smooth muscle cell, especially in view of the fact that CRP co-localizes with monocytes/macrophages and foam cells in the human atherosclerotic lesion.16Torzewski 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: 1386-1392Crossref PubMed Scopus (498) Google Scholar, 17Yasojima K Schwab C McGeer EG McGeer PL Generation of C-reactive protein and complement components in atherosclerotic plaques.Am J Pathol. 2001; 158: 1039-1051Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 18Torzewski M Rist C Mortensen RF Zwaka TP Bienek M Waltenberger J Koenig W Schmitz G Hombach V Torzewski J C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis.Arterioscler Thromb Vasc Biol. 2000; 20: 2094-2099Crossref PubMed Scopus (546) Google Scholar In addition CRP and complement fragments are chemotactic for monocytes/macrophages,18Torzewski M Rist C Mortensen RF Zwaka TP Bienek M Waltenberger J Koenig W Schmitz G Hombach V Torzewski J C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis.Arterioscler Thromb Vasc Biol. 2000; 20: 2094-2099Crossref PubMed Scopus (546) Google Scholar, 29Torzewski J Bowyer DE Waltenberger J Fitzsimmons C Processes in atherogenesis: complement activation.Atherosclerosis. 1997; 132: 131-138Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar which express Fcγ receptors and complement receptors at high levels. Fcγ receptors and complement seem to be involved in CRP-mediated opsonization of LDL.19Zwaka TP Hombach V Torzewski J C-reactive protein-mediated low density lipoprotein uptake by macrophages.Circulation. 2001; 103: 1194-1197Crossref PubMed Scopus (777) Google Scholar Therefore, it might be hypothesized that LDL, CRP, complement, and macrophages orchestrate an inflammatory process in the arterial wall that promotes atherogenesis. In vitro studies have been supplemented by in vivo investigations, with contradictory results. It is important to note here that the most broadly available animal model, ie, the mouse, is considered useless regarding the study of CRP functions because CRP is not an acute phase reactant in mice. To overcome this problem, a transgenic mouse that overexpresses human CRP was generated, and this model has been used to study the role of CRP in cardiovascular disease.30Paul A Ko WS Li L Yechoor V McCrory MA Szalai AJ Chan L C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.Circulation. 2004; 109: 647-655Crossref PubMed Scopus (344) Google Scholar, 31Danenberg HD Szalai AJ Swaminathan RV Peng L Chen Z Seifert P Fay WP Simon DI Edelman ER Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice.Circulation. 2003; 108: 512-515Crossref PubMed Scopus (258) Google Scholar, 32Hirschfield GM Gallimore JR Kahan MC Hutchinson WL Sabin CA Benson GM Dhillon AP Tennent GA Pepys MB Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice.Proc Natl Acad Sci USA. 2005; 102: 8309-8314Crossref PubMed Scopus (181) Google Scholar, 33Trion A de Maat MP Jukema JW van der Laarse A Maas MC Offerman EH Havekes LM Szalai AJ Princen HM Emeis JJ No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-Leiden/human C-reactive protein transgenic mice.Arterioscler Thromb Vasc Biol. 2005; 25: 1641-1646Crossref PubMed Scopus (107) Google Scholar Whereas two initial publications suggested an active contribution of CRP to atherosclerosis and acute cardiovascular events in this model,30Paul A Ko WS Li L Yechoor V McCrory MA Szalai AJ Chan L C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.Circulation. 2004; 109: 647-655Crossref PubMed Scopus (344) Google Scholar, 31Danenberg HD Szalai AJ Swaminathan RV Peng L Chen Z Seifert P Fay WP Simon DI Edelman ER Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice.Circulation. 2003; 108: 512-515Crossref PubMed Scopus (258) Google Scholar two more recent studies have detected no effect.32Hirschfield GM Gallimore JR Kahan MC Hutchinson WL Sabin CA Benson GM Dhillon AP Tennent GA Pepys MB Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice.Proc Natl Acad Sci USA. 2005; 102: 8309-8314Crossref PubMed Scopus (181) Google Scholar, 33Trion A de Maat MP Jukema JW van der Laarse A Maas MC Offerman EH Havekes LM Szalai AJ Princen HM Emeis JJ No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-Leiden/human C-reactive protein transgenic mice.Arterioscler Thromb Vasc Biol. 2005; 25: 1641-1646Crossref PubMed Scopus (107) Google Scholar It is difficult to determine which of the reports is right or wrong, valid or invalid, because the model itself encounters several problems. Human CRP is a foreign antigen in the mouse with many uncertainties concerning its functional role in the immune system of these animals. The situation becomes even more complicated when these mice are crossed with ApoE-deficient mice that obviously lack a fully functional complement system.34Reifenberg K Lehr HA Baskal D Wiese E Schaefer SC Black S Samols D Torzewski M Lackner KJ Husmann M Blettner M Bhakdi S Role of C-reactive protein in atherogenesis. Can the apolipoprotein E knockout mouse provide the answer?.Arterioscler Thromb Vasc Biol. 2005; 25: 1635-1640Crossref PubMed Scopus (89) Google Scholar To cut a long discussion short, it may be appropriate to say that it was worth generating these model systems but hardly possible to answer definitively whether CRP actively contributes to human atherogenesis or not. In this context the article by Sun and colleagues1Sun H Koike T Ichikawa T Hatakeyama K Shiomi M Zhang B Kitajima S Morimoto M Watanabe T Asada Y Chen YE Fan J C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.Am J Pathol. 2005; 167: 1139-1148Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar published in this issue of The American Journal of Pathology may be of considerable interest. The authors use well established animal atherosclerosis models, ie, both cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits, as models to study the role of CRP in atherogenesis. Interestingly, it is the rabbit again, and thus the same species that stopped scientific interest in the matter more than 20 years ago,13Rowe IF Walker LN Bowyer DE Soutar AK Smith LC Pepys MB Immunohistochemical studies of C-reactive protein and apolipoprotein B in inflammatory and arterial lesions.J Pathol. 1985; 145: 241-249Crossref PubMed Scopus (30) Google Scholar that attracts our attention today. Being experts in working with this animal model, the authors elaborate three major results. First, CRP levels are significantly elevated in hypercholesterolemic rabbits. Second, elevated CRP levels strongly correlate with the extent of atherosclerosis in these animals. Third, CRP is ubiquitously present in atherosclerotic lesions in rabbits, and this lesional CRP is derived from the circulation rather than being synthesized locally in the arterial wall. These results are similar in both cholesterol-fed and WHHL rabbits, and each point is well established through analysis of a large number of animals. The article certainly does not prove a causal involvement of CRP in atherogenesis, and even though CRP is an acute-phase reactant in rabbits, many questions concerning CRP functions in these animals remain to be resolved.1Sun H Koike T Ichikawa T Hatakeyama K Shiomi M Zhang B Kitajima S Morimoto M Watanabe T Asada Y Chen YE Fan J C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.Am J Pathol. 2005; 167: 1139-1148Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar The article does, however, describe models that may help address important issues that hint to the third point we raised in the introduction to this commentary: is CRP inhibition with specific drugs a modality to treat atherosclerosis? Four major strategies of CRP inhibition are feasible: 1) transcriptional inhibition of hepatic CRP synthesis,6Ivashchenko Y Kramer F Schaefer S Bucher A Veit K Hombach V Busch A Ritzeler O Dedio J Torzewski J The protein kinase C-pathway is involved in C-reactive protein synthesis in human hepatocytes.Arterioscler Thromb Vasc Biol. 2005; 25: 1-7Google Scholar 2) anti-sense strategies,35Crooke RM Graham MJ Lemonidis KM Whipple CP Koo S Perera RJ An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis.J Lipid Res. 2005; 46: 872-884Crossref PubMed Scopus (204) Google Scholar 3) blockage of CRP-mediated complement activation, and 4) blockage of CRP receptor(s). Pharmaceutical companies are currently examining these strategies. The article by Sun and colleagues1Sun H Koike T Ichikawa T Hatakeyama K Shiomi M Zhang B Kitajima S Morimoto M Watanabe T Asada Y Chen YE Fan J C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.Am J Pathol. 2005; 167: 1139-1148Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar in this issue of The American Journal of Pathology provides in vivo models that may be appropriate to test future CRP inhibitors. If these compounds do not, in parallel, affect LDL levels, discrimination between LDL and CRP effects on atherogenesis may be possible. Finally, these rabbit models might be appropriate for examining bioavailability, specificity, and toxicology of various treatments. In awareness of the controversial discussion and the controversial data on CRP and atherosclerosis, I would like to finish with a personal opinion from a cardiologist's perspective. We should try to inhibit CRP for the treatment of atherosclerosis; otherwise, we might miss a chance to help our patients suffering from cardiovascular disease.
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