VPH-06188; No of Pages 7 Vascular Pharmacology xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph

Review

Biological actions of pentraxins Gemma Vilahur a,⁎, Lina Badimon a,b a b

Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain Cardiovascular Research Chair, UAB, Barcelona, Spain

a r t i c l e

i n f o

Article history: Received 15 January 2015 Received in revised form 15 April 2015 Accepted 2 May 2015 Available online xxxx Keywords: Pentraxins CRP PTX3 Innate immune system Inflammation Cardiovascular disease

a b s t r a c t The innate immunity is the first defense reaction against microorganisms or altered self-components upon tissue injury. Such exogenous or modified endogenous molecules present conserved molecular structures that are recognized by the immune system via pattern-recognition receptors or molecules. Within the soluble pattern-recognition molecules pentraxins play an important role in humoral innate immunity. Pentraxins branch off into the short and long pentraxins. Short constituents include C-reactive protein (CRP) and serum amyloid P-component which are synthesized in the liver mostly upon IL-6 stimulation. Long constituent pentraxin3 (PTX3) is produced by several immune and vascular cells in response to pro-inflammatory signals (but not IL-6) and by toll-like receptor engagement. The ability of pentraxins to interact with numerous ligands (microorganisms, the complement system, dead cells, modified plasma proteins, cellular receptors, extracellular matrix components, and growth factors) supports their involvement in multiple biological functions. As such, the capability of CRP and PTX3 to modulate inflammation through the complement system and innate immunity suggests their contribution in atherosclerosis, thrombosis, and ischemic heart disease. In this review we will overview the key properties of pentraxins and discuss the major relevant findings that attribute to pentraxins, particularly CRP and PTX3, a biological role in the pathogenesis of cardiovascular disease. © 2015 Elsevier Inc. All rights reserved.

Contents Pentraxins: fluid-phase endogenous modulators of the humoral innate immune response Pentraxins structure, synthesis, and regulation . . . . . . . . . . . . . . . . . . . Pentraxins: biological actions and implications in cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Pentraxins interaction with the complement system . . . . . . . . . . . . . 3.2. Pentraxins in atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Pentraxins in ischemic heart disease . . . . . . . . . . . . . . . . . . . . 3.4. Pentraxins in angiogenesis and restenosis . . . . . . . . . . . . . . . . . . 3.5. Pentraxins in thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2. 3.

1. Pentraxins: fluid-phase endogenous modulators of the humoral innate immune response The innate immune system comprises the first line of defense mechanism against invading pathogens or endogenous molecules exposed ⁎ Corresponding author at: Cardiovascular Research Center, C/Sant Antoni Mª Claret 167, 08025 Barcelona, Spain. Tel.: +34 93 5537100; fax: +34 93 556 55 59. E-mail address: [email protected] (G. Vilahur).

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and/or released upon tissue injury. Such exogenous agents or altered self-structures present highly conserved molecular configurations, collectively referred to as pathogen-associated molecular patterns (PAMPs), which are recognized by the immune system via pattern recognition molecules (PRMs) or pathogen recognition receptors (PRRs) [1]. PRMs and/or PRRs may either be cell-associated or fluid-phase molecules. Cell-associated molecules include toll-like receptors, scavenger receptors, and nucleotide-binding oligomerization domain-like receptors, whereas fluid-phase molecules consist of ficolins, collectins, and

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pentraxins. The latter play a key role in the humoral innate immune response and the resulting inflammatory process both critical components of cardiovascular disorders [2]. 2. Pentraxins structure, synthesis, and regulation Pentraxins are a superfamily of multimeric proteins characterized by the presence of a ≈ 200 amino acid domain (pentraxin signature) in their C-terminal region [3]. Depending on the length of the N-terminal region pentraxins are classified as being constituents of the short [C-reactive protein (CRP) and serum amyloid P component (SAP)] or long [pentraxin 3 (PTX3)] pentraxin subfamily. CRP was identified in 1930 [4], SAP was discovered in 1965 [5], and PTX3 in the early 1990s [6]. Since then, other long pentraxins have been identified including neuronal pentraxin-1 and -2, neuronal pentraxin receptor, and most lately pentraxin 4 [7]. CRP is mainly found in the circulation as a pentamer formed by five identical non-glycosylated and non-covalently associated 23-kDa protomers (206 amino acids long) arranged in an annular configuration with cyclin pentameric symmetry [8]. However, upon dissociation of its pentameric quaternary structure, CRP subunits undergo a spontaneous and irreversible conformational change. The resulting molecule, termed modified or monomeric CRP (mCRP) has reduced aqueous solubility and becomes a tissue-based rather than a soluble-based molecule [9]. As such, mCRP has been detected in human aortic and carotid atherosclerotic plaques although not in healthy vessels [10,11]. SAP is a glycoprotein also made up of five non-covalently associated structures (23-kDa each) which may form a decameric structure under certain conditions but not in serum [12,13]. Finally, PTX3 forms an octamer structure with intra-molecule disulfide bonds. Inflammation, infection or tissue damage triggers a non-specific acute phase response in which the synthesis of a number of plasma proteins (around 40) is rapidly augmented in response to inflammatory mediators originated at the site of the pathology. Among them CRP and PTX3 are the most characteristic acute phase proteins in humans. Other acute phase proteins include coagulation proteins (fibrinogen,

prothrombin, Factor VIII, plasminogen), complement factors (C1s, C2, C3, C4, C5, B, C1 inhibitor), proteinase inhibitors (alpha-1 antitrypsin, alpha-1 antichymotrypsin), and transport proteins (haptoglobin, hemopexin, ceruloplasmin) [8]. Conversely, other plasma proteins have shown to markedly diminish their presence in the acute phase response [albumin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), properdin, and transthyretin]. Pentraxin SAP has been shown to remain invariant in humans (30–50 mg/L) although markedly rises in the acute phase response in mice [14]. CRP and SAP are primarily produced in the liver in response to inflammatory mediators such as interleukin (IL)-1, IL-17 and most prominently IL-6 (Fig. 1) [15]. In contrast, PTX3 is produced by different cell types (vascular cells and innate immune cells) but not hepatocytes and pro-inflammatory cytokines IL-1β and TNFα (but not IL-6), toll-like receptors agonists, and distinct microbial moieties or intact microorganisms enhance PTX3 production (Fig. 2). Interestingly, atheroprotective HDL and anti-inflammatory IL-10 have also demonstrated to modulate PTX3 expression suggesting a regulatory role of PTX3 in the anti-/pro- inflammatory balance [16–18]. Specifically, HDL3 subfraction has been shown to induce PTX3 production in endothelial cells and subsequently abrogate cytokine-induced inflammation. This atheroprotective effect likely occurs through PI3K/Akt pathway activation via G-coupled lysosphingolipids receptor-1 (S1P) [16]. On the other hand, anti-inflammatory IL-10 has also shown to amplify PTX3 expression on stimulated immune cells [19]. As an acute phase protein, CRP is barely detectable in the plasma of healthy human adults (levels below 3 mg/L) but rises rapidly (6 h) and markedly (up to 1000-fold) reaching a maximum at 48 h following an acute phase stimulus. CRP quickly drops once the triggering factor has been eliminated. PTX3 also presents low circulating levels under physiological conditions (below 2 ng/mL) and peaks earlier than CRP (at around 6 h) reaching levels of 10 ng/mL after tissue injury [e.g., acute myocardial infarction (AMI)] and of 1500 ng/mL upon inflammatory or septic conditions [20]. The rapid increase in PTX3 is likely derived from its local production by a number of different cell sources as compared to IL-6-related hepatic synthesis of CRP. Moreover, there is

Fig. 1. Mechanisms involved in C-reactive protein (CRP) synthesis and/or release and the subsequent contribution to the etiopathogenesis of atherosclerosis. mCRP: monomeric or modified CRP. EC: endothelial cells; EPC: endothelial progenitor cells; VSMCs: vascular smooth muscle cells; ICAM: intracellular adhesion molecule; IL: interleukin; MMP: metalloproteinases; VCAM: vascular adhesion molecule; MCP-1: monocyte chemoattractant protein-1; NO: nitric oxide; VSMCs: vascular smooth muscle cells.

Please cite this article as: Vilahur G, Badimon L, Biological actions of pentraxins, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.05.001

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Fig. 2. Mechanisms involved in pentraxin3 (PTX3) synthesis and/or release and potential functions on the myocardium and vasculature. TLR: toll-like receptors; HDL: high density lipoproteins; LDL: low-density lipoproteins; IL: interleukin; LPS: lipopolysaccharide; VSMCs: vascular smooth muscle cells; MLB: mannose-binding lectin; C1: complement 1.

also a constitutive form of PTX3 stored in specific granules of neutrophils that guarantees such early and functionally competent delivery of PTX3 upon inflammatory activation [21]. 3. Pentraxins: biological actions and implications in cardiovascular disease Pentraxins are capable of binding to and interacting with different ligands playing a key role in several biological actions (Fig. 3). Autologous ligands include damaged cell membranes, modified plasma proteins, apoptotic cells, phospholipids, and nuclear components whereas extrinsic ligands include microorganisms' constituents such as glycans and phospholipids. The impact of pentraxins on cardiovascular disease (CVD) has been evidenced in the modulation of complement activation, innate immunity and inflammation (Figs. 1, 2 and 4). For further review articles on non-cardiovascular pentraxin-related biological actions please refer to Agrawal et al. [22]. Circulating levels of pentraxins, particularly CRP and PTX3, have been related to CVD including atherosclerosis, thrombosis and AMI. As such, elevated concentrations of CRP (usually assessed as high sensitivity CRP) are predictive of future vascular morbidity (e.g. fatal and nonfatal cardiovascular and cerebrovascular events) [23] and data collected so far support PTX3 for becoming a new candidate prognostic marker for CVD [24]. In this regard, the Cardiovascular Health Study [25] reported an association between PTX3 levels and the incidence of coronary artery diseases (CAD) and all-cause mortality in CAD patients. These associations were independent of CRP and other classical risk factors. Moreover, in AMI patients' prognostic value of PTX3 in three-month mortality post-event was superior to that provided by CRP, creatinine kinase, Troponin-T and the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) [24]. Finally, SAP is used in routine clinical diagnosis for systemic amyloidosis assessment. Despite the widespread use of pentraxins as disease biomarkers it remains uncertain whether they play a causal role in atherogenesis and its clinical consequences.

It must be stated that the physiopathological role of CRP in the cardiovascular system has been hampered by the evolutionary divergence between CRP in mouse and humans. Mice produce weak CRP levels even during inflammation whereas human CRP does not interact with the classical complement cascade (C1q component) in mice. This has hampered the rigorous genetic testing of its role in vivo and only the administration of exogenous CRP has allowed investigating CRP-mediated effects. In contrast, PTX3 has been highly conserved in evolution in terms of sequence, gene organization, and regulation which has allowed addressing pathophysiological questions using genetically-modified mice. 3.1. Pentraxins interaction with the complement system Pentraxins (mostly CRP and PTX3) interaction with the complement system has broad implications for host defense against microbial infections, regulation of the inflammatory reaction and dead cells removal. The activation of the complement system leads to several biological responses including activation and chemotaxis of leukocytes with the resulting inflammatory response, opsonization and pathogen/immune complexes phagocytosis, and lysis of target cells (Fig. 4). The complement system, consisting of about 20 components in blood plasma and 10 regulators or receptors on cell membranes, can be activated through three pathways: the classical, the alternative, and the mannose-binding lectin (MBL) pathway (Fig. 4). The classical activation cascade may be initiated by binding of CRP to C1q with the subsequent formation of C3 convertase thereby participating in leukocyte recruitment and activation (Fig. 4). Evidence suggests that CRP has little activation on the terminal complex C5b to C5b-9 limiting the strong inflammatory responses typically associated with the membrane attack complex. Bound CRP may also provide a binding site for the soluble control protein factor H thereby regulating the alternative-pathway amplification and C3 convertase. On the other hand, PTX3 has been shown to exert divergent effects on complement activation by modulating all three complement

Please cite this article as: Vilahur G, Badimon L, Biological actions of pentraxins, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.05.001

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Fig. 3. Biological functions of short [C-reactive protein (CRP) and serum amyloid P protein (SAP)] and long [pentraxin3 (PTX3)] pentraxins that result from their binding and interaction with multiple ligands.

pathways. PTX3 may bind the complement component C1q resulting in the activation of the classical pathway. This only takes place when C1q is found immobilized (e.g., bound on a microbial surface) [26] and occurs

in a glycosylation-dependent manner. As such, unglycosylated PTX3 has been shown to more efficiently bind C1q inducing a higher level of complement activation [27]. In contrast, when PTX3-C1q interaction occurs

Fig. 4. Activation of the complement system and the subsequent biological responses (gray squares). Three pathways through which complement can be activated are currently recognized: the classical, alternative, and mannose-binding lectin (MBL) pathways (white squares). The classical activation cascade is most commonly initiated by binding of immune complexes, pentraxins or other ligands to C1q. The initial stage of activation generates cleavage products of C3 which act as leukocyte activators and chemoattractants (inflammatory mediators) or opsonins (phagocytosis). Activation of C5b–6 to C5b–9 generates powerful chemotactic peptides and favors the formation of the membrane attack complex, which can result in lysis of the target pathogens or cells. Complement activation by PTX3 and CRP is majorly restricted to C1 complex although they have also the ability to interact with factor H, resulting in the regulation of the alternative pathway, and PTX3 to bind to MBL regulating the lectin pathway.

Please cite this article as: Vilahur G, Badimon L, Biological actions of pentraxins, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.05.001

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in the fluid-phase, PTX3 can sequester C1q and prevent complement activation [28]. In addition, PTX3 can also interact with Factor H and MBL also modulating the other two complement pathways (Fig. 4) [29]. 3.2. Pentraxins in atherosclerosis Pentraxins have been detected within advanced human atherosclerotic plaques suggesting to play an active role in atherogenesis [11,13, 30]. Clinical studies using intravascular ultrasound (IVUS) virtual histology (VH) have reported that high CRP concentrations are associated with a higher coronary plaque burden and the presence of large lesions but not with the presence of thin-cap fibroatheroma lesions. These data suggest a role for CRP in the evolution from stable coronary plaque to unstable plaque [31]. In line with these findings, an interesting study in human coronary artery specimens revealed that CRP and PTX3 are more enhanced in unstable than in stable coronary plaques [32]. Studies from our group and others have also demonstrated that CRP and PTX3 distribution within the atherosclerotic lesions distinctly differs [11,32]. For instance: 1) PTX3 and not CRP is augmented in complicated plaques compared to fibroatheroma whereas CRP but not PTX3 is more accumulated in fibroatheroma than in atheroma; 2) PTX3 is found to be quite sparse in lipid-rich regions of the fibroatheroma lesions whereas CRP is found to be particularly intense surrounding and within the lipid core; 3) PTX3 and CRP colocalize with macrophages but PTX3 and not CRP correlates with the extent of M2 macrophage phenotype (presents anti-inflammatory properties); and, 4) although PTX3 is notably abundant in areas of intraplaque hemorrhage where CRP is scarce, CRP has been strongly detected around areas of newly formed microvessels suggesting CRP contribution to neovascularization [11,33,34]. Overall, these observations suggest that CRP and PTX3 may play distinct biological roles in atherosclerosis and ensuing thrombotic complications. Several in vitro studies have supported, by using commercial CRP (cCRP) and cultured endothelial cells that CRP acts as a proatherosclerotic factor. In fact, cCRP has been shown to up-regulate angiotensin type 1 receptors, reduce the expression of endothelial nitric oxide synthase (eNOS), increase apoptosis, induce the expression of adhesion molecules and chemokines secretion, and to stimulate metalloproteinases (1 and 10) production in endothelial cells (Fig. 1) [35–39]. However, other investigators have questioned the reliability of these in vitro findings and have attributed these cellular effects to the presence of contaminants present in CRP preparations (endotoxins, azide, and other additives) rather than to CRP itself [14]. In fact, extensive dialysis of CRP or azide removal has been shown to abrogate IL-6 and MCP-1 induction and eNOS expression, respectively [40, 41]. Finally, the impact of CRP of endothelial progenitor cells (EPC) biology has also been explored reporting the capability of CRP to inhibit EPC survival, function, and differentiation [42]. As per PTX3, multiple cells including monocytes/macrophages, neutrophils, and activated endothelial cells are capable of releasing PTX3 upon stimulation by IL-1 and TNF-α, cytokines markedly expressed in atherosclerotic lesions [21,30,43–46]. Moreover, atherogenic modified LDLs (i.e., oxidized LDLs) have also been shown to stimulate PTX3 expression in vascular smooth muscle cells (VSMCs). However, further studies are needed to ascertain whether pentraxins exert pro- or antiinflammatory effects and their contribution to atherogenesis. So far, high plasma PTX3 has been linked with vascular endothelial dysfunction in several human diseases [47]. In fact, plasma pentraxin 3 is considered to more accurately predict endothelial dysfunction than highsensitive CRP [48]. Moreover, a recent experimental study has provided the first evidence of a direct role of PTX3 on vascular function. As such, Carrizzo et al. [49] have demonstrated that PTX3 induces dysfunction and morphological changes of endothelial cells through a P-selectin/ MMP1 pathway which in turn converges on nitric oxide signaling. Moreover, the authors have also demonstrated that PTX3 administration to mice is associated with endothelial dysfunction and increased blood pressure [49].

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3.3. Pentraxins in ischemic heart disease The involvement of pentraxins as a pathogenic factor in ischemic heart damage is also under debate. Little evidence exists as to the role of CRP in ischemic heart disease. So far, in vivo data have reported the effect of CRP to promote inflammation and cardiac fibrosis [50]. We have shown that infiltrated macrophages at the border site of the cardiac ischemic lesion express mCRP [51]. Moreover, cardiac mCRP expression peaks at reperfusion and remains increased up to one-week after AMI suggesting a potential role in perpetuating and/or amplifying the inflammatory process likely contributing to cardiac remodeling [52]. In this regard, CRP has been shown to interact with extracellular matrix components (e.g., fibronectin) [53]. On the other hand, the presence of PTX3 in cardiomyocytes remains controversial some studies reporting its presence in healthy intact myocardium [20] whereas others only upon cardiac injury [54]. In this latter regard, the detection of PTX3 in infarcted hearts supports a pathophysiological role of the protein in myocardial damage and repair. A study in a model of coronary artery ligation/reperfusion damage revealed larger myocardial infarcts in PTX3deficient mice which were associated with increased no-reflow area, neutrophils and macrophages myocardial recruitment, reduced angiogenesis, and enhanced apoptosis in cardiomyocytes [55]. Of note, PTX3-deficient mice showed no difference in infarct size in the absence of reperfusion supporting that PTX3 modulates the ischemia/reperfusion injury [55]. A potential cardioprotective effect of PTX3 may take place through the modulation of the complement cascade activation (Figs. 2 and 4). In this regard, increased complement C3 detection delimiting the injured area has been detected in PTX3-deficient mice [55]. PTX3 has been shown to compete with leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) for the interaction with P-selectin dampening neutrophils recruitment and extravasation at sites of inflammation thereby restricting the expansion of the inflammatory response (Fig. 2) [56]. Certainly, neutrophils infiltration into the ischemic tissue may act as a double edge sword participating in tissue repair but also, via release of inflammatory mediators, further promote tissue damage, as observed in ischemia/reperfusion [57]. PTX3 binding to P-selectin has also shown to prevent platelet–platelet and platelet–leukocytes interactions thereby diminishing platelet/leukocyte aggregates and the no-reflow phenomenon (defective tissue oxygenation of the jeopardized myocardium despite successful coronary revascularization; Fig. 2). Hence, overall, data published so far suggest a cardiac protective effect of PTX3 by dampening the inappropriate and exaggerated inflammatory response. 3.4. Pentraxins in angiogenesis and restenosis A role for pentraxins in the context of angiogenesis and vascular restenosis has also been described. It has been hypothesized PTX3 ability to inhibit new blood vessel formation, VSMC proliferation and migration, intimal thickening, and restenosis. The mechanisms behind these beneficial effect rely on the high affinity of PTX3 to bind fibroblastgrowing-factor 2 (FGF2; Fig. 2). PTX3 interaction with FGF2 hampers FGF2 interaction with tyrosine kinase receptors (FGFRs) and the subsequent formation of the FGF/FGFR system, a complex critically involved in angiogenesis and vascular remodeling. Indeed, FGF/FGFR system has been shown to modulate VSMC proliferation, migration, and survival in cell culture conditions and neointimal thickening and restenosis in animal models of carotid balloon catheter injury [58,59]. In contrast, as stated above, mCRP seems to exert pro-angiogenic effects since it is found to surround new microvessels in advanced atherosclerotic plaques [11,33,34]. We have demonstrated mCRP ability to promote angiogenesis either in vitro (endothelial cell migration, proliferation and tubulogenesis) or in vivo (chorioallantoic membrane assay) and have determined the main CRP-induced pro-angiogenic genes [34]. In addition, a recent study has demonstrated the ability of CRP to promote angiogenesis via activation of the PI3K/Akt survival pathway [60].

Please cite this article as: Vilahur G, Badimon L, Biological actions of pentraxins, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.05.001

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3.5. Pentraxins in thrombosis

References

CRP has contrasting effects on thrombus formation depending on its conformation [61,62]. We reported that whereas native or pentameric CRP (pCRP) exerts no effect on thrombus formation, mCRP significantly enhances platelet activation, adhesion, and thrombus growth under arterial flow conditions (Fig. 1) [63]. Moreover, we provided evidence that the dissociation of circulating blood pCRP into mCRP may occur on the surface of activated platelets and it is dependent on the thrombogenic potency of the triggering substrate and the exposure of platelet glycoprotein (GP) IIb–IIIa receptor [64]. Alternatively, pCRP has also been shown to convert into mCRP under static conditions, over immobilized adenosine diphosphate-activated platelet membranes, and apoptotic cells [10,65]. Furthermore, a recent study has suggested that circulating microparticles derived from activated cell membranes may also induce pCRP dissociation [66]. Altogether, these findings seem to support that both mCRP bound to activated cell membranes and mCRP present within the advanced atherosclerotic plaque may play a critical role in thrombus formation and propagation upon mechanical or spontaneous atherosclerotic plaque rupture [11]. Finally, SAP has been shown to increase platelet deposition on fibrin monolayers (but not over collagen substrates), activated platelets or under flow conditions [64,67] and, PTX3 interaction with P-selectin has been shown to limit platelet activation and aggregation [56].

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4. Concluding remarks Pentraxins are pivotal fluid-phase components of the humoral arm of the innate immune system being CRP and PTX3 the prototypic molecules representative of the short and long pentraxin family, respectively. Increased plasma levels of both are observed in patients with AMI and atherosclerosis supporting their use as clinical biomarkers in the context of CVD. Yet, their direct contribution to the pathophysiological mechanisms underlying vascular or tissue damage is still under intense research. The ability of pentraxins to bind and interact with multiple ligands underscores their implications in different biological actions. As such, pentraxins have been shown to act as modulatory molecules of the innate immune response, complement activation, inflammation, angiogenesis, no-reflow phenomena, vascular remodeling, platelet activation, and thrombus formation, all of which are critical players in vascular pathology and ischemic heart disease. However, whether they act as fine-tuners of inflammation dampening an excessive inflammatory reaction or are just amplifiers of the innate immune response remains to be fully explored. Although still debated, substantial evidence suggests that CRP contributes to atherosclerosis progression by exerting pro-inflammatory effects and data collected so far indicate PTX3 ability to act at the crossroad between anti- and pro-inflammatory signals regulating the immune-inflammatory response. In addition, not all the pentraxins have the same effect on angiogenesis or thrombus formation. Pharmacological modulation of mCRP and/or PTX3 may show their contribution to CVD. Certainly, the pharmacological relevance of targeting pentraxins and the molecular mechanisms involved deserve further investigation. In this regard, an interesting recent study has demonstrated the ability of atorvastatin to reduce PTX3 expression in vascular cells via the inhibition of protein geranylgeranylation [68]. Acknowledgments The work presented in this review has been partially financed by PNS 2012-40208 (to GV) and PNS 2013-42962-R (to LB) from the Spanish Ministry of Science and Innovation and the Red Investigación Cardiovascular RD12/0042/0027 (Spanish Cardiovascular Network) from Instituto Salud Carlos III (to LB). We thank Fundacion Jesus Serra, Barcelona for the continuous support. GV is a ‘Ramon y Cajal’ scientist funded by the Spanish Ministry of Science and Innovation (MICINN).

Please cite this article as: Vilahur G, Badimon L, Biological actions of pentraxins, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.05.001

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Please cite this article as: Vilahur G, Badimon L, Biological actions of pentraxins, Vascul. Pharmacol. (2015), http://dx.doi.org/10.1016/ j.vph.2015.05.001

Biological actions of pentraxins.

The innate immunity is the first defense reaction against microorganisms or altered self-components upon tissue injury. Such exogenous or modified end...
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