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Cardiovascular Research 71 (2006) 30 – 39 C-reactive protein in atherosclerosis: A causal factor? aHemostasis and Thrombosis Research Centre, Dept. of Hematology, Leiden University Medical Centre, Leiden, The Netherlands bDepartment of Hematology, Room Ee 13.93, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands Received 3 August 2005; received in revised form 3 March 2006; accepted 6 March 2006 Atherosclerosis is considered a to be multifactorial disease driven by inflammatory reactions. The process of inflammation also contributes to the pathogenesis of acute atherothrombotic events. C-reactive protein (CRP) is an acute phase protein and its concentration inserum reflects the inflammatory condition of the patient. Levels of CRP are consistently associated with cardiovascular disease (CVD) andpredict myocardial infarctions and stroke. Since CRP is present in the atherosclerotic lesion, it may actively contribute to the progression and/or instability of the atherosclerotic plaque. The role of CRP in inflammation and its causality in atherosclerosis are the subject of manyinvestigations but are not yet fully elucidated. This review focuses on recently identified mechanisms by which CRP may modulate andevolve the process of atherosclerosis. We discuss the function of CRP and review the most recent evidence for an independent role of CRP inthe development of atherosclerosis. Many studies suggest such a role, but a number of the described effects may be the result ofcontamination of the CRP preparations.
D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: C-reactive protein; Azide; Atherosclerosis; Inflammation; Thrombosis predictive value in the pathogenesis of CVD. Many clinicaland population studies, with cross-sectional and nested Inflammation plays a key role in the pathogenesis of case – control designs, proved these inflammatory mediators cardiovascular disease (CVD), acute atherothrombotic events and atherosclerosis Inflammation also regu- Several reports describe human CRP to be involved in lates the production of the acute phase proteins such as C- the induction of ischemic tissue damage in the brain, reactive protein (CRP), fibrinogen and serum amyloid A myocardial infarction and the increase of stroke volume in The serum concentration of CRP can increase > 1000- Most clinical studies report that CRP is an independent fold upon inflammation and, with a half life of 19 h, CRP is predictor of risk of atherosclerosis cardiovascular a very stable downstream marker of the inflammatory process Because CRP is such a sensitive indicator of the myocardial infarction even after considering other inflammatory process, it has been extensively studied cardiovascular risk factors such as age, smoking, obesity, whether plasma concentrations of CRP and other circulating diabetes, hypercholesterolemia and hypertension. However, inflammatory proteins (e.g. fibrinogen, interleukin-6) have a absence of a relationship between CRP and risk ofmyocardial infarction has been reported as well, especiallyafter comprehensive adjustment for established risk factors An early indication that CRP may be more than just a * Corresponding author. Tel.: +31 10 4089448; fax: +31 10 4089470.
risk marker was the observation that, of several inflamma- 0008-6363/$ - see front matter D 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 tory markers studied (such as P-selectin, interleukin-6, the development, instability and eventual rupture of the interleukin-1, tumor necrosis factor-a (TNFa), soluble intercellular adhesion molecule-1 (sICAM-1), fibrinogen),CRP emerged as the most powerful inflammatory predictorof future cardiovascular risk Assuming that, in the physiological condition of human pathology and the atherosclerotic lesion, CRP exerts direct CRP is one of the substances present in the atheroscle- functions, the question is whether it is possible to rotic lesion, more specifically in the vascular intima, where discriminate between the direct effects of CRP and the it co-localizes with monocytes, monocyte-derived macro- parallel presence of other factors that determine the risk of phages and lipoproteins This localization makes a CVD. It was recently observed that several of the direct contribution to the atherosclerotic process possible.
biological effects contributed to CRP in vitro are in fact CRP is a phylogenetically highly conserved plasma caused by contamination of the CRP preparation by azide protein, with homologues in vertebrates and many inverte- or bacterial lipopolysaccharides However, in other brates, that is part of the systemic response to inflammation studies a contribution of contamination can be excluded, It is an acute phase protein and a member of the family indicating that a causal role of CRP is clearly present.
of pentraxins. CRP was originally observed in 1930 in the Examples are the recent ex vivo and in vivo studies plasma of patients with acute infections, where it reacted where CRP was administered to healthy volunteers with the C polysaccharide of pneumococcus and the in vitro experiments on the effect of CRP on The major part of the CRP present in the plasma comes tissue plasminogen activator activity, interleukin-1h and from the liver, where the synthesis of CRP is mainly tumor necrosis factor-a in human aortic endothelial cells regulated by interleukin-6, which in turn is upregulated by The functional effects of CRP that may be relevant other inflammatory cytokines such as interleukin-1 and for the development of CVD and will be discussed in this tumor necrosis factor-a Small amounts of CRP can also be produced locally For example, CRP has beendetected on the surface of about 4% of normal bloodlymphocytes and it has been demonstrated that this CRP is produced by the lymphocytes themselves CRP alsocan be produced locally in atherosclerotic lesions by SMCs The first step in the development of an atherosclerotic plaque and the resulting local inflammatory process is The structure of CRP is important for its stability and for endothelial dysfunction. Upon injury, endothelial cells the execution of its function CRP is composed of (ECs) express the vascular cell adhesion molecule-1 five identical, 21,500 Da subunits. Upon dissociation of its (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) pentameric structure, CRP subunits undergo a spontaneous and the endothelial leukocyte adhesion molecule-1 and irreversible conformational change. The loss of the (ELAM) on the cell surface Leukocytes, especially pentameric structure of CRP results in modified or T-lymphocytes (CD8+ cytotoxic T-cells, CD4+ helper Th1/ monomeric CRP (mCRP), which is a naturally occurring Th2-cells) and monocytes, are then recruited from the form of CRP and it is a tissue-based rather than a serum- blood and cross the endothelial cell barrier via a process based molecule mCRP is less soluble than CRP and called diapedesis. Lipoprotein particles (LDLs and var- tends to aggregate, and it has been described to induce iants such as oxidized LDL) accumulate in the lesion, are mRNA of chemokines and the expression of adhesion taken up by monocyte-derived macrophages, which as a molecules in human cultured coronary artery endothelial result develop into foam cells, and form a fatty streak.
cells (HCAECs) Thus, next to circulating native Smooth muscle cells (SMCs) proliferate and extracellular pentameric CRP, mCRP can also promote a pro-inflamma- matrix components extend to form a fibrous cap, tory phenotype and exert atherogenic effects in human enclosing and defining the morphology of the atheroscle- endothelial cells, although it may be in less potent manner than native CRP In ApoE(À/À) mice, mCRP has been The cells involved in formation of the atherosclerotic described to have opposite effects on atherosclerosis plaque (e.g. ECs, monocytes, T-cells, SMCs) are stimulated compared to normal CRP These data may explain in to produce many different substances, such as inflamma- part the conflicting activities previously reported for CRP in tory mediators (interleukin-6, tumor necrosis factor-a, interleukin-1) complement factors (C1q, C3, C5 –C9) chemokines (monocyte chemoattractant pro-tein-1, interleukin-8), adhesive molecules (selectins P/E, 4. Functionality of CRP and purity of CRP preparations integrins CD18/CD11) metalloproteinases (MMP-1/9)collagenases, reactive oxygen species (such as nitric The assumption that CRP is a causal factor in the oxide (NO)) and CRP These mediators contribute to development of the atherosclerotic lesion is based on its E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 rapid accessibility to the plaque, localization in the plaque rosis. Therefore, in this review, we will discuss the possible and the results of in vitro studies, in which CRP has been direct roles of CRP in atherosclerosis.
demonstrated to actively contribute to inflammatory pro-cesses.
The involvement of CRP in several mechanisms execut- ing and maintaining the inflammatory process has beenwidely studied with the use of different commercially Inflammatory mechanisms play a central role in all human CRP preparations. These CRP preparations differ phases of atherosclerosis, from the initial recruitment of in source (serum, plasma, recombinant) and quality.
circulating leukocytes to the arterial wall to the rupture of Use of commercially CRP preparations introduces two unstable plaques, which results in the clinical manifestations means of interference: 1) by contamination with bacterial of the disease. CRP may be involved in each of these stages lipopolysaccharides (LPS) or 2) by contamination with the by direct influencing processes like complement activation, apoptosis, vascular cell activation, monocyte recruitment, Presence of endotoxin in commercially available CRP lipid accumulation and thrombosis. Each of these processes preparations has been eloquently described and we offers several mechanisms by which CRP may influence its ourselves measured concentrations between 3 and 600 pg progress, as will be described in more detail below.
endotoxin/100 Ag CRP in different purified and recombinantCRP preparations (with the Limulus Amebocyte test which is endotoxin-positive > 10 pg = 0.12 EU endotoxin present;unpublished data 2003). The presence of even very low Activation of the classical pathway of the complement concentrations of endotoxin can interact with the contents of system is a well known and direct biological function of the vessel wall activate gene expression and a cascade CRP Via this action, CRP directly amplifies and of reactions in monocytes activate procoagulant activity facilitates innate immunity a process that has in monocytes and macrophages through induction of already been associated with initiation and progression of tissue factor Endotoxins trigger an atherogenic re- CVD for a long time. In situ hybridization showed intense sponse in SMCs and block the induction of secretion of mRNA signals for CRP and complement component C4 in interleukin-1 and MCP-1 by human endothelial cells SMCs and macrophages present in the thickened intima of The amount of sodium azide present in different the lesion. CRP also co-localizes with C5 – C9, the commercially CRP preparations, varies from 0.05% to membrane attack complex, of complement Activation 1.00% of the CRP present. Recent studies describe an of this membrane attack complex (MAC) is initiated by the effect of this preservative, when tested in vitro, on several direct binding of CRP to C1q, also present in the processes involved in atherosclerotic development, which atherosclerotic lesion and characterized by elevated were formerly subscribed to CRP. Addition of sodium azide, levels of component C5a C5a itself exerts potent in amounts comparable to its concentration as a preserva- chemotactic and pro-inflammatory effects and its plasma tive, to cultures of endothelial cells resulted in a decrease of levels have been associated with increased cardiovascular migration, proliferation and angiogenic properties of these risk in patients with advanced atherosclerosis cells In SMCs, addition of sodium azide (without CRP is also involved in the inhibition of complement CRP) did induce vasorelaxation and evoked inducible activation through interaction with factor H (fH), which is nitric oxide synthase (iNOS) induction and nitric monoxide also present in injured areas. The CRP – fH complex (NO) release. These effects were initially ascribed to the interferes with the activity of C3b (see and CRP. It is not clear yet how many of the reported effects of thus will prevent formation of the MAC.
CRP can be ascribed to contamination and whether the Through the interaction with complement factors, CRP effects can be explained by contamination completely or exerts a direct effect on arterial endothelial cells, by whether there will simultaneous effects of contaminants and increasing the expression of complement inhibitory factors CRP. However, several studies showed direct effects of CRP on the endothelial cells. This suggests that CRP-mediated preparations that were free of contaminants, showing that complement activation is a system set to regulate the CRP may indeed have a direct role. Examples are studies inflammatory reaction, because it will result in promoting comparing the effect of plasma from CRP transgenic mice the removal of debris from tissues and the deleterious effects and wild-type mice or studies in which the effect of of complement activation in patients with CVD CRP containing a sodium azide contamination exceeds the However, since complement activation also leads to the effect of sodium azide alone which deliver strong production of a variety of pro-inflammatory molecules, this evidence of CRP having a direct and causal effect on several mechanism of CRP-mediated complement regulation might cell types and the inflammatory processes. Furthermore, the also aggravate the inflammatory status in the entire body as specific interaction of CRP with complement factors, cell well as in the atherosclerotic plaque. Therefore, the direct receptors, lipids and other inflammatory mediators assures interaction between CRP and complement can both activate the possibility of CRP being directly involved atheroscle- and inhibit inflammation in atherosclerotic lesions.
E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 Fig. 1. Schematic representation of CRP-mediated complement regulation. Binding of CRP to microbial polysaccharides or ligands exposed on damagedactivates the classical pathway of complement. Activation is however limited to C1, C4, C2 and C3 with little consumption of C5 – C9. Surface-bound CRPrecruits fH, which regulates complement activation at the level of the alternate pathway C3 convertase and C5 convertase of both the classical and alternatepathways. fH is therefore thought to be responsible for low consumption of terminal pathway components during the CRP-initiated complement activation(adapted from Giannakis et al. fH: factor H, MBL: mannose-binding lectin pathway of complement, MAC: membrane attack complex.
5.2. Interaction with cell surface receptors CRP through its interference with the binding of LDL toCD36 The close proximity of CRP to monocytic cells in the arterial intima, attenuates its possibilities for a direct contribution to the progression of atherosclerosis.
The observation that CRP is localized between monocytes Thrombosis contributes to the progression of the underlines the possibility of a direct interaction of CRP atherosclerotic lesion and to the precipitation of the with these cells and with monocyte-derived macrophages cardiovascular event. Direct actions of CRP which contrib- via binding to a specific receptor. CRP binds to several ute to the induction of a prothrombotic state may be the receptors on human monocytes; to FcRgIIa (CD32) with enhancement of the procoagulant activity or the high affinity and to FcRgI (CD64) with lower affinity reduction of fibrinolysis CRP has been suggested to increasing phagocytosis and the release of inflam- induce a prothrombotic state via induction of tissue factor matory cytokines The Fc receptors have been expression in human monocytes but only in the described to mediate the effect of CRP on human aortic presence of and through direct interaction with other blood endothelial cells FcRgIIa is known as the putative cells as T-lymphocytes, B-lymphocytes and natural killer CRP receptor for leukocytes and also has been found on bovine aortic endothelial cells CRP also binds to In transgenic mice expressing human CRP (hCRP), the the inhibitory receptor, FcgammaRIIb, blocking activating injury-induced occlusion of the femoral artery (75% after 28 signals The binding of CRP to a receptor suggests days) was enhanced compared to the amount of occlusion its capacity to induce a specific biological effect observed in wild-type mice (17% after 28 days) such as direct involvement in cell-mediation and opsoni- indicating a prothrombotic effect of hCRP. A direct effect zation. Addition of CRP with and without anti-CD32- of CRP on hemostasis was shown in a recent study, where antibody to endothelial cells demonstrated the partial recombinant human CRP was infused into human volun- mediation of CRP in regulation of cell surface protein teers, which resulted in the stimulation of both hemostasis expression, such as the endothelial protein C receptor, by CD32 However, the downstream effects of CRP CRP may also inhibit fibrinolysis by increasing the binding have not yet been elucidated. The interaction of expression and activity of the main inhibitor of fibrinolysis, CRP with CD36, a scavenger receptor which is expressed plasminogen activator inhibitor-1 (PAI-1) in human aortic by macrophages and is involved in uptake of low-density endothelial cells (HAEC) Since PAI-1 promotes lipoprotein particles (LDL), demonstrates a direct role of atherothrombosis and progression of acute coronary syn- E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 dromes, this effect of CRP may also affect CVD Also, promotes MCP-1 mediated chemotaxis through upregula- besides this effect on PAI-1, recently CRP has been tion of CC chemokine receptor 2 expression in human demonstrated to directly decrease antigen levels and the activity of tissue plasminogen activator (tPa) in HAEC. tPa The effect of CRP on T-lymphocytes is indirect. T- is the substance normally inhibited by PAI-1. In this study, lymphocytes are recruited to the atherosclerotic lesion as a the direct and specific role of CRP is demonstrated by using result of the ongoing inflammatory process. Through the CRP that was free from sodium azide and LPS contamina- stimulation of cytokine production and secretion by macro- phages, CRP exerts an indirect effect on T-lymphocytespresent in the atherosclerotic lesion. CRP induces macro- 5.4. Cellular modulation, recruitment and activation phages to express interleukin-12, which contributes to thedevelopment of CD4+ T-helper cells In turn, these cells CRP contributes to an arterial pro-inflammatory and pro- express interferon-g, which is synergistic with CRP in the atherosclerotic phenotype by directly upregulating adhesion execution of many functions contributing to the pro- molecules and chemoattractant chemokines in endothelial atherosclerotic phenotype. In contrast, during CRP induced cells, vascular SMCs and monocytic cells. On the activation of complement and opsonization of apoptotic endothelial cell surface, expression of adhesion molecules cells, the actively phagocyting macrophages reduce expres- such as ICAM-1, VCAM-1, and E-selectin is upregulated sion of IL-12 and thereby suppress T-lymphocytes by CRP Via these processes, CRP induces plateletadhesion to endothelial cells CRP stimulates endo- 5.5. Expression of inflammatory mediators: cytokines, thelial cell dysfunction and the recruitment of monocytes and T-lymphocytes towards the endothelial wall. Thesefindings were reported by several groups, who also showed CRP induces inflammatory cytokines in a dose-depen- that CRP induced monocyte chemoattractant chemokine-1 dent way which provides further support for the (MCP-1) production. This upregulation of adhesion mole- hypothesis that interaction with mononuclear phagocytes cules is partly mediated via the production of endothelin-1, constitutes an important biological role for this acute phase a potent endothelium-derived vasoactive factor, and by the protein. Quantitative analysis of the CRP-induced release of production of the inflammatory cytokines interleukin-6 and interleukin-6, interleukin-1 and tumor necrosis factor-a by interleukin-8. As to the effects of CRP on MCP-1 freshly isolated normal human monocytes, revealed slight expression, aortic endothelial cells seem to be unresponsive differences in time courses. All three cytokines were whereas venous endothelial cells or monocytes detected 4 h after CRP addition in vitro, with maximal show increased expression of this chemoattractant. Since levels of TNFa at 8 h and of interleukin-1 and interleukin-6 atherosclerosis mainly develops in the arteries, the clinical significance of the effect of CRP on venous cells is not Interleukin-8 (IL-8), a member of the CXC chemokines promotes monocyte – endothelial cell adhesion and arrest CRP is also known to activate the NF-nB signaling and is abundant in atherosclerotic plaques. In human aortic pathway in saphenous vein endothelial cells which, in endothelial cells in vitro, CRP increases IL-8 protein and recent light of possible azide contamination might be mRNA expression in a time- and dose-dependent manner an artefact. Also in vascular SMCs, CRP has been indicated via specific upregulation of NF-nB activity to activate NF-nB Therefore, CRP has been suggested CRP induces production and secretion of MCP-1 in to mediate proliferation and activation of vascular SMCs, human umbilical vein endothelial cells but not in aortic causing the accumulation of these cells in the vascular endothelial cells MCP-1 present in the atherosclerotic intima, which is a key event in the development of arterial lesion can also originate from monocytes. CRP induces lesions. Another manner in CRP directly affects the a 7-fold increase in the production of monocyte MCP-1 in activation and proliferation of vascular SMCs, is via purified peripheral monocytes In patients with acute upregulation of mRNA and protein and increased cell coronary syndromes, baseline level of this chemoattractant surface expression of the angiotensin type 1 receptor (AT1- were elevated. This elevated expression is associated with R). This was demonstrated in vitro in human vascular both traditional risk factors for atherosclerosis as well as SMCs and in vivo in a rat carotid artery angioplasty model increased risk of myocardial infarction, independent of CRP also appears to be involved in the infiltration of In atherosclerotic lesions, CRP directly upregulates monocytes into the vessel wall and their subsequent mRNA expression of the macrophage markers CD11b and development into foam cells. The deposition of CRP in HLA-DR, as well as their protein products the arterial wall precedes monocyte infiltration and direct Monocyte expression of CD11b increased significantly involvement of CRP in recruitment of blood monocytes up to twofold when exposed to CRP, while no significant has been demonstrated in vitro, suggesting CRP to be difference in CD32 expression was observed, whereas CRP chemotactic for human blood monocytes CRP also exposure decreases CD31 expression. CRP can affect E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 monocyte activation ex vivo and induce phenotypic changes that result in an altered recruitment to endothelial cells Another mechanism by which CRP influences the CRP is directly involved in the process of apoptosis development and maintenance of the athereosclerotic lesion It binds to apoptotic cells in a Ca2+-dependent is its involvement in the CD40 – CD40Ligand (CD40L or manner and augments the classical pathway of complement CD154) interaction. CD40L, a 33-kDa activation-induced T- activation but protects the cells from assembling the lymphocyte surface glycoprotein, binds to CD40, a phos- terminal complement components (C5 – C9). Furthermore, phorylated glycoprotein expressed on B-lymphocytes, vas- CRP enhances opsonization and phagocytosis of apoptotic cular endothelial cells, monocytes, macrophages and cells by macrophages associated with the expression of the fibroblasts. Like CRP, the amount of soluble CD40 anti-inflammatory cytokine transforming growth factor-h.
increases during inflammation and in the atherosclerotic CRP and the classical complement components act in lesion. Therefore CD40L has been suggested to be a marker concert to promote non-inflammatory clearance of apoptotic for inflammation and involved in risk of cardiovascular cells The inhibitory effect of CRP on the NO events as well CRP upregulates the cell surface expression of endothelial progenitor cells directly inhibits expression of CD40 and CD40L on human umbilical their mobilization and differentiation, survival and function, endothelial cells in time CD40L is shed into the whereby it facilitates EC apoptosis and blocks the process of vasculature. Elevated levels of this soluble CD40L angiogenesis Apoptosis of vascular SMCs also plays (sCD40L) identify patients with acute coronary syndromes an important role in progression of atherosclerotic lesions at increased risk of recurrent MI and death, independent of and contributes to increased plaque vulnerability. Silencing other variables as cardiac troponine T or CRP the CRP-regulated GADD153 gene in vascular SMCsindicated that CRP plays an essential role in induced CRP also binds to phosphatidylcholines, by which it CRP has been described to decrease the expression and participates directly in activation of macrophages and bioactivity of endothelial nitric oxide synthase (eNOS or neutrophils in the clearance of apoptotic and necrotic cells NOS3) which results in reduced bioavailability of However, neutrophils are not present in the nitric monoxide (NO) and a subsequent effect of vasodila- tation. It was demonstrated recently that this effect can becaused by sodium azide as well however, it is not clear whether there remains a role for CRP. It is thereforeuncertain whether there is a causal role for CRP in the The interaction between lipids and CRP is diverse. It has regulation of expression of NO and involvement in vascular been suggested that CRP could be the factor that links reactivity Nevertheless, CRP has been suggested to lipoprotein-deposition and complement activation in ath- exert a specific effect on endothelial eNOS expression erosclerotic plaques. Binding of tissue-deposited CRP to through binding to the CRP receptor FcRgIIa In enzymatically degraded LDL enhances complement activa- HAECs and human coronary artery endothelial cells tion, which may be relevant to the development and (HCAECs), CRP contributes to a proatherogenic and progression of the atherosclerotic lesion, particularly at prothrombotic state by decreasing the release of NO and early stages of atherosclerosis when low concentrations of of the vasodilator and inhibitor of platelet aggregation enzymatically degraded LDL are present And, prostacyclin (PGI2), through directly increasing both although direct involvement of CRP has not been demon- strated, through this binding of CRP to enzymatically In vascular smooth muscle cells, CRP reduces expression degraded LDL, CRP may be involved in the massive of the inducible variant of nitric oxide synthase (iNOS) release of MCP-1 from macrophages described to be caused and subsequent NO-synthesis as well. But again, this might be an artefact caused by sodium azide In these vascular Although the reports on interaction between CRP and ox- SMCs, CRP also has been described to induce activation of LDL are conflicting, complement activation as a result of the iNOS promoter which, despite the fact that CRP this interaction is generally considered unlikely. Neverthe- seems to be no more than a weak inducer of NO-production, less, CRP has been described to directly induce lectin-like contradicts the study of Ikeda and coworkers. Nevertheless, ox-LDL receptor-1 expression (LOX-1) in human aortic both studies demonstrate that CRP is likely to be involved in ECs, because this could be reduced with antibodies against the regulation of cellular NO-levels. Furthermore, interac- CD32/CD64, ET-1 or IL-6 Via LOX-1, CRP is tion between CRP and interferon-gamma appears to suggested to regulate monocytes adhesion to ECs and enhance the effect of CRP on NO-regulation, which indicates that there may be a direct effect of CRP because The majority of sub-endothelial foam cells show contaminants will not be able to exert these specific positive staining for CRP. Zwaka et al. demonstrated that native LDL that was co-incubated with CRP was taken up E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 by macrophages via macropinocytosis. It was concluded process was not possible but we discussed above that that foam cell formation in human atherogenesis might be one thing does not exclude the other.
caused in part by uptake of CRP-opsonized native LDL Recently, several studies have reported conflicting results on the direct contribution of CRP to atherosclerosis in mice High levels of high-density lipoprotein (HDL) are that transgenically expressed CRP. Since CRP is expressed atheroprotective since HDL is involved in transporting only at a very low concentration in mice and does not show cholesterol from the periphery to the liver. HDL might also an acute phase behavior, it is possible to study the role of protect the endothelium since the CRP-induced upregulation transgenic CRP in mice. The first report was from Paul and of inflammatory adhesion molecules in HUVECs was coworkers who observed larger aortic atherosclerotic lesions completely blocked by HDL. So, HDL neutralizes CRP in human CRP transgenic apolipoprotein (apo) E-knockout induced proinflammatory activity HDL also inhibits mice than in control mice but in this study the CRP atherosclerosis through prevention of oxidation of LDL. It is levels were very high. Recently, we did not see a difference not known whether CRP has an effect on the oxidative in lesion size or severity of atherosclerosis at the aortic root between apoE*3-Leiden mice that did express human CRP(< 10 mg/L) and controls Reifenberg and coworkersreported similar observations in apoE-knockout mice that expressed rabbit CRP and subsequently discussedwhether transgenic apoE-knockout mice would provide an CRP may contribute to development of the atheroscle- answer about the role of CRP in atherogenesis at all. In our rotic lesion and the subsequent acute cardiovascular events opinion, we believe that more studies are needed to via its role in a large number of biological pathways. And elucidate the differences, and we cannot ignore previous although a number of the effects of CRP may be clouded by studies in which mouse models were used to clearly contamination, we demonstrated that a direct role of CRP in demonstrate a direct role of CRP in atherogenesis many inflammatory processes is probable. We reviewed the In conclusion, it is now an established fact that elevated roles of CRP in complement activation, cell adhesion and CRP levels are associated with a worse prognosis for CVD, recruitment, thrombosis, the expression of regulatory such as myocardial infarction, stroke and unstable angina.
cytokines, apoptosis and lipids. All these mechanisms are But it is important to distinguish between a role as a marker part of or are compromised by the process of inflammation.
and a factor that directly causes a biological effect because CRP may thus contribute to the development of the this will determine the optimal therapeutic intervention.
atherosclerotic lesion via a direct pro-inflammatory effect.
CRP may be a causal factor as well as a marker for CRP increases the release of endothelin-1 and upregulates inflammation, depending on the concentration. This concen- adhesion molecules and chemoattractant chemokines in tration of CRP depends on the rates of production and endothelial cells and vascular SMC. Most studies focus on clearance. The fact that CRP is a very stable protein, which is the effects of CRP on aortic endothelial cells but a few not consumed to a significant extent in any process, and the studies have also determined the effect on venous endothe- clearance of which is not influenced by any known condition lial cells as HUVECS and it was observed that CRP induced is in agreement with its functioning as a causal factor, the expression of MCP-1 CD40 and increased attempting to prolong the stability of the atherosclerotic activity of NF-nB This suggests that CRP exerts different and specific effect on different cell types.
In the atherosclerotic lesion, many processes involving However, it is important to realize that CRP also exerts CRP and many different cell types have been described but activity in anti-inflammatory or so-called protective mech- there is also concern that part of the observed effects are not anisms, such as suppressing the formation of the C5 – C9 mediated by CRP itself, but are the result of contamination of complex. Thereby CRP is capable of maintaining a certain the preparations with endotoxin or azide. Therefore, currently balance in the inflammatory process and stability of the the exact role of CRP in the initiation and progression of atherosclerotic lesion. In the lesion, CRP, which stimulates atherosclerosis is still unclear and needs to be further studied.
immunity as well as inflammation, contributes to theprolongation of the stability of the plaque.
A low level of chronic inflammation is represented by CRP levels that are only slightly, but for a prolonged period,increased and these levels characterize CRP as a predictor of We thank Prof. R. M. Bertina for critical reading of the a cardiovascular event. On the other hand, a high concentration of CRP (> 10 mg/L) can be measured for ashorter period during the acute phase where it is involved in the inflammatory defense process. It has been suggestedthat, because of this expression of high levels of CRP, a [1] Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med direct biological or a causal function in the atherosclerotic E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 [2] Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis.
[22] Kasper HU, Schmidt A, Roessner A. Expression of the adhesion molecules ICAM, VCAM, and ELAM in the arteriosclerotic plaque.
[3] Gabay C, Kushner I. Acute-phase proteins and other systemic Gen Diagn Pathol 1996;141:289 – 94.
responses to inflammation. N Engl J Med 1999;340:448 – 54.
[23] Ross R. Atherosclerosis is an inflammatory disease. Am Heart J [4] Uhlar CM, Whitehead AS. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 1999;265:501 – 23.
[24] Libby P, Sukhova G, Lee RT, Galis ZS. Cytokines regulate vascular [5] Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem functions related to stability of the atherosclerotic plaque. J Cardio- vasc Pharmacol 1995;25(Suppl 2):S9 – 12.
[6] Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, [25] Seifert PS, Hansson GK. Complement receptors and regulatory C-reactive protein, albumin, or leukocyte count with coronary heart proteins in human atherosclerotic lesions. Arteriosclerosis 1989; disease: meta-analyses of prospective studies. JAMA 1998; [26] Speidl WS, Exner M, Amighi J, Kastl SP, Zorn G, Maurer G, et al.
[7] Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, et Complement component C5a predicts future cardiovascular events in al. C-reactive protein, a sensitive marker of inflammation, predicts patients with advanced atherosclerosis. Eur Heart J 20052294 – 9.
future risk of coronary heart disease in initially healthy middle-aged [27] Kassirer M, Zeltser D, Prochorov V, Schoenman G, Frimerman A, men: results from the MONICA (Monitoring Trends and Determi- Keren G, et al. Increased expression of the CD11b/CD18 antigen on nants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to the surface of peripheral white blood cells in patients with ischemic 1992. Circulation 1999;99:237 – 42.
heart disease: further evidence for smoldering inflammation in [8] Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concen- patients with atherosclerosis. Am Heart J 1999;138:555 – 9.
tration of interleukin-6 and the risk of future myocardial infarction [28] Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of among apparently healthy men. Circulation 2000;101:1767 – 72.
matrix metalloproteinases and matrix degrading activity in vulnerable [9] Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH.
regions of human atherosclerotic plaques. J Clin Invest 1994; Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation [29] Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth [10] Gill R, Kemp JA, Sabin C, Pepys MB. Human C-reactive protein muscle cells. Circulation 2003;108:1930 – 2.
increases cerebral infarct size after middle cerebral artery occlusion [30] Lombardo A, Biasucci LM, Lanza GA, Coli S, Silvestri P, Cianflone in adult rats. J Cereb Blood Flow Metab 2004;24:1214 – 8.
D, et al. Inflammation as a possible link between coronary and [11] Libby P, Ridker PM. Inflammation and atherosclerosis: role of C- carotid plaque instability. Circulation 2004;109:3158 – 63.
reactive protein in risk assessment. Am J Med 2004;116(Suppl [31] Torzewski J, Torzewski M, Bowyer DE, Frohlich M, Koenig W, Waltenberger J, et al. C-reactive protein frequently colocalizes with [12] Pepys MB, Hirschfield GM. C-reactive protein and atherothrombo- the terminal complement complex in the intima of early atheroscle- rotic lesions of human coronary arteries. Arterioscler Thromb Vasc [13] Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM.
C-reactive protein and the risk of developing hypertension. JAMA [32] Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for [14] Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C- atherosclerosis. Circulation 2001;103:1194 – 7.
reactive protein and low-density lipoprotein cholesterol levels in the [33] Tillett WS, Francis T Jr. Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus. J Exp Med 1930; [15] Doggen CJ, Berckmans RJ, Sturk A, Manger Cats V, Rosendaal FR.
[34] Castell JV, Gomez-Lechon MJ, David M, Fabra R, Trullenque R, C-reactive protein, cardiovascular risk factors and the association Heinrich PC. Acute-phase response of human hepatocytes: regulation with myocardial infarction in men. J Intern Med 2000;248:406 – 14.
of acute-phase protein synthesis by interleukin-6. Hepatology [16] Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB.
Production of C-reactive protein and risk of coronary events in stable [35] Ishikawa T, Imamura T, Hatakeyama K, Date H, Nagoshi T, and unstable angina. European Concerted Action on Thrombosis and Kawamoto R, et al. Possible contribution of C-reactive protein Disabilities Angina Pectoris Study Group. Lancet 1997;349:462 – 6.
within coronary plaque to increasing its own plasma levels across [17] Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein coronary circulation. Am J Cardiol 2004;93:611 – 4.
and other markers of inflammation in the prediction of cardiovascular [36] Kuta AE, Baum LL. C-reactive protein is produced by a small disease in women. N Engl J Med 2000;342:836 – 43.
number of normal human peripheral blood lymphocytes. J Exp Med [18] Liu C, Wang S, Deb A, Nath KA, Katusic ZS, McConnell JP, et al.
Proapoptotic, antimigratory, antiproliferative, and antiangiogenic [37] Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C- effects of commercial C-reactive protein on various human endothe- reactive protein and complement components in atherosclerotic lial cell types in vitro: implications of contaminating presence of plaques. Am J Pathol 2001;158:1039 – 51.
sodium azide in commercial preparation. Circ Res 2005;97:135 – 43.
[38] Shrive AK, Cheetham GM, Holden D, Myles DA, Turnell WG, [19] Taylor KE, Giddings JC, van den Berg CW. C-reactive protein- Volanakis JE, et al. Three dimensional structure of human C-reactive induced in vitro endothelial cell activation is an artefact caused by protein. Nat Struct Biol 1996;3:346 – 54.
azide and lipopolysaccharide. Arterioscler Thromb Vasc Biol 2005; [39] Verma S, Szmitko PE, Yeh ET. C-reactive protein: structure affects function. Circulation 2004;109:1914 – 7.
[20] Bisoendial RJ, Kastelein JJ, Levels JH, Zwaginga JJ, van den [40] Diehl EE, Haines GK, Radosevich JA, Potempa LA. Immunohisto- Boogaard B, Reitsma PH, et al. Activation of inflammation and chemical localization of modified C-reactive protein antigen in coagulation after infusion of C-reactive protein in humans. Circ Res normal vascular tissue. Am J Med Sci 2000;319:79 – 83.
[41] Khreiss T, Jozsef L, Potempa LA, Filep JG. Conformational [21] Singh U, Devaraj S, Jialal I. C-reactive protein decreases tissue rearrangement in C-reactive protein is required for proinflammatory plasminogen activator activity in human aortic endothelial cells: actions on human endothelial cells. Circulation 2004;109:2016 – 22.
evidence that C-reactive protein is a procoagulant. Arterioscler [42] Devaraj S, Venugopal S, Jialal I. Native pentameric C-reactive Thromb Vasc Biol 2005;25:2216 – 21.
protein displays more potent pro-atherogenic activities in human E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 aortic endothelial cells than modified C-reactive protein, Atheroscle- [63] Bharadwaj D, Stein MP, Volzer M, Mold C, Du Clos TW. The major rosis; in press, Corrected Proof, Available online 13 May 2005.
receptor for C-reactive protein on leukocytes is fcgamma receptor II.
[43] Schwedler SB, Amann K, Wernicke K, Krebs A, Nauck M, Wanner C, et al. Native C-reactive protein increases whereas modified C- [64] Escribano-Burgos M, Lopez-Farre A, del Mar GM, Macaya C, reactive protein reduces atherosclerosis in apolipoprotein E-knockout Garcia-Mendez A, Mateos-Caceres PJ, et al. Effect of C-reactive mice. Circulation 2005;112:1016 – 23.
protein on Fcgamma receptor II in cultured bovine endothelial cells.
[44] Pepys MB, Hawkins PN, Kahan MC, Tennent GA, Gallimore JR, Graham D, et al. Proinflammatory effects of bacterial recombinant [65] Nan B, Yang H, Yan S, Lin PH, Lumsden AB, Yao Q, et al. C- human C-reactive protein are caused by contamination with reactive protein decreases expression of thrombomodulin and bacterial products, not by C-reactive protein itself. Circ Res 2005; endothelial protein C receptor in human endothelial cells. Surgery [45] Osterud B. Interaction of endotoxins, blood elements and the vessel [66] Penn MS, Topol EJ. Tissue factor, the emerging link between wall. Prog Clin Biol Res 1985;189:67 – 79.
inflammation, thrombosis, and vascular remodeling. Circ Res 2001; [46] Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal 2001;13:85 – 94.
[67] Libby P, Simon DI. Inflammation and thrombosis: the clot thickens.
[47] Rivers RP, Hathaway WE, Weston WL. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 1975; [68] Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial [48] Jungi TW, Miserez R, Brcic M, Pfister H. Change in sensitivity to infarction or sudden death in patients with angina pectoris. ECAT lipopolysaccharide during the differentiation of human monocytes to Study Group. European Concerted Action on Thrombosis and macrophages in vitro. Experientia 1994;50:110 – 4.
Disabilities. Circulation 1996;94:2057 – 63.
[49] Mackman N. Lipopolysaccharide induction of gene expression in [69] Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, human monocytic cells. Immunol Res 2000;21:247 – 51.
Sharrett AR, et al. Fibrinolytic activation markers predict myocardial [50] Nagoshi Y, Kuwasako K, Cao YN, Kitamura K, Eto T. Effects of C- infarction in the elderly. The Cardiovascular Health Study. Arte- reactive protein on atherogenic mediators and adrenomedullin in rioscler Thromb Vasc Biol 1999;19:493 – 8.
human coronary artery endothelial and smooth muscle cells.
[70] Whisler RL, Proctor VK, Downs EC, Mortensen RF. Modulation of Biochem Biophys Res Commun 2004;314:1057 – 63.
human monocyte chemotaxis and procoagulant activity by human C- [51] van den Berg CW, Taylor KE, Lang D. C-reactive protein-induced in reactive protein (CRP). Lymphokine Res 1986;5:223 – 8.
vitro vasorelaxation is an artefact caused by the presence of sodium [71] Nakagomi A, Freedman SB, Geczy CL. Interferon-gamma and azide in commercial preparations. Arterioscler Thromb Vasc Biol lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein: relationship with age, sex, and hormone replace- [52] Brill A, Yaron G, Dashevsky O, Danenberg H, Varon D. CRP ment treatment. Circulation 2000;101:1785 – 91.
induces platelet adhesion to endothelial cells under flowPoster ISTH [72] Paffen E, Vos HL, Bertina RM. C-reactive protein does not directly induce tissue factor in human monocytes. Arterioscler Thromb Vasc [53] Pepys MB, Hirschfield GM. C-reactive protein: a critical update.
[73] Danenberg HD, Szalai AJ, Swaminathan RV, Peng L, Chen Z, Seifert [54] Volanakis JE, Kaplan MH. Interaction of C-reactive protein com- P, et al. Increased thrombosis after arterial injury in human C-reactive plexes with the complement system: II. Consumption of guinea pig protein-transgenic mice. Circulation 2003;108:512 – 5.
complement by CRP complexes: requirement for human C1q.
[74] Lip GY, Blann AD, Farooqi IS, Zarifis J, Sagar G, Beevers DG.
Sequential alterations in haemorheology, endothelial dysfunction, [55] Szalai AJ, van Ginkel FW, Wang Y, McGhee JR, Volanakis JE.
platelet activation and thrombogenesis in relation to prognosis Complement-dependent acute-phase expression of C-reactive protein following acute stroke: the West Birmingham Stroke Project. Blood and serum amyloid P-component. J Immunol 2000;165:1030 – 5.
Coagul Fibrinolysis 2002;13:339 – 47.
[56] Giannakis E, Male DA, Ormsby RJ, Mold C, Jokiranta TS, [75] Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen Ranganathan S, et al. Multiple ligand binding sites on domain activator inhibitor-1 expression and activity in human aortic seven of human complement factor H. Int Immunopharmacol 2001; endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 2003;107:398 – 404.
[57] Szalai AJ, Agrawal A, Greenhough TJ, Volanakis JE. C-reactive [76] Pasceri V, Wu HD, Willerson JT, Yeh ET. Modulation of vascular protein: structural biology and host defense function. Clin Chem Lab inflammation in vitro and in vivo by peroxisome proliferator- activated receptor-gamma activators. Circulation 2000;101:235 – 8.
[58] Reynolds GD, Vance RP. C-reactive protein immunohistochemical [77] Pasceri V, Chang J, Willerson JT, Yeh ET. Modulation of C-reactive localization in normal and atherosclerotic human aortas. Arch Pathol protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation [59] Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J, et al. C-reactive protein in the arterial intima: role [78] Thomassen MJ, Meeker DP, Deodhar SD, Wiedemann HP, Barna BP.
of C-reactive protein receptor-dependent monocyte recruitment in Activation of human monocytes and alveolar macrophages by a atherogenesis. Arterioscler Thromb Vasc Biol 2000;20:2094 – 9.
synthetic peptide of C-reactive protein. J Immunother 1993;13:1 – 6.
[60] Crowell RE, Du Clos TW, Montoya G, Heaphy E, Mold C. C- [79] Verma S, Badiwala MV, Weisel RD, Li SH, Wang CH, Fedak PW, et reactive protein receptors on the human monocytic cell line U-937.
al. C-reactive protein activates the nuclear factor-kappaB signal Evidence for additional binding to Fc gamma RI. J Immunol 1991; transduction pathway in saphenous vein endothelial cells: implica- tions for atherosclerosis and restenosis. J Thorac Cardiovasc Surg [61] Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005;117:104 – 11.
[80] Hattori Y, Matsumura M, Kasai K. Vascular smooth muscle cell [62] Devaraj S, Du Clos TW, Jialal I. Binding and internalization of C- activation by C-reactive protein. Cardiovasc Res 2003;58:186 – 95.
reactive protein by Fcgamma receptors on human aortic endothelial [81] Wang CH, Li SH, Weisel RD, Fedak PW, Dumont AS, Szmitko P, et cells mediates biological effects. Arterioscler Thromb Vasc Biol al. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation 2003;107:1783 – 90.
E. Paffen, M.P.M. deMaat / Cardiovascular Research 71 (2006) 30 – 39 [82] Han KH, Hong KH, Park JH, Ko J, Kang DH, Choi KJ, et al. C- [98] Ikeda U, Takahashi M, Shimada K. C-reactive protein directly reactive protein promotes monocyte chemoattractant protein-1- inhibits nitric oxide production by cytokine-stimulated vascular mediated chemotaxis through upregulating CC chemokine receptor smooth muscle cells. J Cardiovasc Pharmacol 2003;42:607 – 11.
2 expression in human monocytes. Circulation 2004;109:2566 – 71.
[99] Lafuente N, Azcutia V, Matesanz N, Cercas E, Rodriguez-Manas L, [83] Yamashita H, Shimada K, Seki E, Mokuno H, Daida H. Concen- Sanchez-Ferrer CF, et al. Evidence for sodium azide as an artifact trations of interleukins, interferon, and C-reactive protein in stable mediating the modulation of inducible nitric oxide synthase by C- and unstable angina pectoris. Am J Cardiol 2003;91:133 – 6.
reactive protein. J Cardiovasc Pharmacol 2005;45:193 – 6.
[84] Kim SJ, Gershov D, Ma X, Brot N, Elkon KB. Opsonization of [100] Blaschke F, Bruemmer D, Yin F, Takata Y, Wang W, Fishbein MC, et apoptotic cells and its effect on macrophage and T cell immune al. C-reactive protein induces apoptosis in human coronary vascular responses. Ann NY Acad Sci 2003;987:68 – 78.
smooth muscle cells. Circulation 2004;110:579 – 87.
[85] Devaraj S, O’keefe G, Jialal I. Defining the pro-inflammatory [101] Gershov D, Kim S, Brot N, Elkon KB. C-reactive protein binds to phenotype using high sensitive C-reactive protein levels as the apoptotic cells, protects the cells from assembly of the terminal biomarker. J Clin Endocrinol Metab 2005;90:4549 – 54.
complement components, and sustains an antiinflammatory innate [86] Ballou SP, Lozanski G. Induction of inflammatory cytokine release immune response: implications for systemic autoimmunity. J Exp from cultured human monocytes by C-reactive protein. Cytokine [102] Du Clos TW. Function of C-reactive protein. Ann Med 2000; [87] Devaraj S, Kumaresan PR, Jialal I. Effect of C-reactive protein on chemokine expression in human aortic endothelial cells. J Mol Cell [103] Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition [88] Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte of a common ligand: phosphorylcholine of oxidized phospholipids.
chemoattractant protein-1 in human atheromatous plaques. J Clin Proc Natl Acad Sci U S A 2002;99:13043 – 8.
[104] Klouche M, Gottschling S, Gerl V, Hell W, Husmann M, Dorweiler [89] de Lemos JA, Morrow DA. Combining natriuretic peptides and B, et al. Atherogenic properties of enzymatically degraded LDL: necrosis markers in the assessment of acute coronary syndromes. Rev selective induction of MCP-1 and cytotoxic effects on human Cardiovasc Med 2003;4(Suppl 4):S37 – 46.
macrophages. Arterioscler Thromb Vasc Biol 1998;18:1376 – 85.
[90] Woollard KJ, Philllips DC, Griffiths HR. Direct modulatory effect of [105] Li L, Roumeliotis N, Sawamura T, Renier G. C-reactive protein C-reactive protein on primary human monocyte adhesion to human enhances LOX-1 expression in human aortic endothelial cells: endothelial cells. Clin Exp Immunol 2002;130:256 – 62.
relevance of LOX-1 to C-reactive protein-induced endothelial [91] Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell dysfunction. Circ Res 2004;95:877 – 83.
[106] Wadham C, Albanese N, Roberts J, Wang L, Bagley CJ, Gamble JR, [92] Lin R, Liu J, Gan W, Yang G. C-reactive protein-induced expression et al. High-density lipoproteins neutralize C-reactive protein proin- of CD40 – CD40L and the effect of lovastatin and fenofibrate on it flammatory activity. Circulation 2004;109:2116 – 22.
in human vascular endothelial cells. Biol Pharm Bull 2004;27: [107] Pepys MB. CRP or not CRP? That is the question. Arterioscler Thromb Vasc Biol 2005;25:1091 – 4.
[93] Varo N, Vicent D, Libby P, Nuzzo R, Calle-Pascual AL, Bernal MR, [108] Paul A, Ko KW, Li L, Yechoor V, McCrory MA, Szalai AJ, et al. C- et al. Elevated plasma levels of the atherogenic mediator soluble reactive protein accelerates the progression of atherosclerosis in CD40 ligand in diabetic patients: a novel target of thiazolidinediones.
apolipoprotein E-deficient mice. Circulation 2004;109:647 – 55.
[109] Trion A, de Maat MP, Jukema JW, van der Laarse A, Maas MC, [94] Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demon- Offerman EH, et al. No effect of C-reactive protein on early stration that C-reactive protein decreases eNOS expression and atherosclerosis development in apolipoprotein E*3-Leiden/human bioactivity in human aortic endothelial cells. Circulation 2002;106: C-reactive protein transgenic mice. Arterioscler Thromb Vasc Biol [95] Swafford Jr AN, Bratz IN, Knudson JD, Rogers PA, Timmerman JM, [110] Reifenberg K, Lehr HA, Baskal D, Wiese E, Schaefer SC, Black S, et Tune JD, et al. C-reactive protein does not relax vascular smooth al. Role of C-reactive protein in atherogenesis: can the apolipoprotein muscle: effects mediated by sodium azide in commercially available E knockout mouse provide the answer? Arterioscler Thromb Vasc preparations. Am J Physiol, Heart Circ Physiol 2005;288:H1786 – 95.
[96] Clapp BR, Hirschfield GM, Storry C, Gallimore JR, Stidwill RP, [111] Ursella S, Mazzone M, Portale G, Testa A, Pignataro G, Covino M, et Singer M, et al. Inflammation and endothelial function: direct al. How to use the C-reactive protein in cardiac disease? Minerva vascular effects of human C-reactive protein on nitric oxide bioavailability. Circulation 2005;111:1530 – 6.
[97] Venugopal SK, Devaraj S, Jialal I. C-reactive protein decreases prostacyclin release from human aortic endothelial cells. Circulation2003;108:1676 – 8.



UNITED STATES DISTRICT COURT MIDDLE DISTRICT OF FLORIDA ORLANDO DIVISION IN RE: Seroquel Products Liability Litigation. Case No. 6:06-md-1769-Orl-22DAB _____________________________________/ TO THE UNITED STATES DISTRICT COURT This cause came on for consideration after hearing on the following motion filed herein: PLAINTIFFS’ MOTION FOR DISCOVERY SANCTIONS (Doc. No. 256)

Fatigue: An Overview Thomas C. RosenThal, mD; BaRBaRa a. majeRoni, mD; RiChaRD PReToRius, mD, mPh, and KhaliD maliK, mD, mBa, Department of Family Medicine, University at Buffalo, Buffalo, New York Fatigue, a common presenting symptom in primary care, negatively impacts work performance, family life, and social relationships. The differential diagnosis of fatigue includes lifestyle issu

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