Original ArticlePTX3 expression in the heart tissues of patients with myocardial infarction and infectious myocarditis
Introduction
C-reactive protein (CRP) and pentraxin 3 (PTX3) are members of the highly conserved pentraxin superfamily [1], [2], [3]. CRP is the classical short pentraxin produced in the liver in response to inflammatory mediators, in particular IL-6, and represents a well-recognized marker of systemic response to local inflammation [4].
PTX3 is a prototypic member of the long pentraxin family; it shares some similarities with CRP, but differs in terms of the presence of an unrelated long N-terminal domain coupled to the C-terminal domain, gene organization, cellular source, and tissue source, inducing stimuli and ligands recognized [3]. PTX3 binds with high affinity to C1q and factor H (participates in the activation and regulation of the complement system), to apoptotic cells, and to extracellular matrix (ECM) components TNFα-induced protein 6 and inter-α-inhibitor [5], [6], [7], [8], [9], [10]. In addition, PTX3 has a nonredundant role in innate resistance to selected pathogens and is also essential in female fertility as it functions by forming the ECM of cumulus oöphorus in ovarian follicles [3], [7], [11], [12], [13]. PTX3 is rapidly produced in damaged tissues by different cells such as fibroblasts, dendritic cells, smooth muscle cells, and, in particular, macrophages and endothelial cells, following several primary proinflammatory signals [e.g., Toll-like receptor (TLR) engagement by microbial moieties, TNFα, and IL-1β] [3], [14]. Recently, PTX3 has been found also in bone marrow myelocytes and in mature neutrophils, but not in basophils and eosinophils: PTX3 is stored in “ready-to-use” form in specific neutrophil granules and is secreted in response to microbial recognition and inflammatory stimuli [15].
Due to the fact that the main tissue cellular sources of PTX3 are macrophages and the endothelium, PTX3 levels may better reflect the inflammatory status of the vascular bed and may represent a rapid marker for local inflammation at sites of vessel injury.
Pentraxins have a well-documented role in the diagnosis of cardiovascular diseases: the association between elevated levels of CRP and an increased risk of cardiovascular events is well established, and the link between PTX3 and ischemic heart disorders is known as well. PTX3 is induced in vascular smooth muscle cells by atherogenic modified low-density lipoproteins and is present in human atherosclerotic lesions [16], [17]. Moreover, recently, we demonstrated that deficiency in PTX3 promotes vascular inflammation and atherosclerosis in a murine model [18]. Plasma PTX3 levels are elevated in patients with unstable angina pectoris [19] and in patients undergoing selective coronary stenting [20]; in heart failure, plasma PTX3 levels correlate with advancing severity of the disease and are an independent predictor of cardiovascular events [21], [22].
In patients with acute myocardial infarction (AMI), PTX3 has been described to represent an early marker of myocardial lesion peaking in plasma at about 7 h after the onset of symptoms [23]; in the same context, plasma CRP peaked later, between 24 and 48 h after the first symptoms. Moreover, in a series of patients with myocardial infarction and ST elevation followed for 3 months, plasma PTX3 had a stronger prognostic value in predicting mortality compared with CRP and other cardiac biomarkers [24].
The cellular sources of circulating levels of PTX3 in cardiovascular diseases are still poorly defined. Studies in mice suggest that, during AMI, PTX3 is induced in the heart in a IL-1R–MyD88-dependent pathway, in particular in neutrophils, macrophages, and the endothelium [25]. However, the rapid release of stored PTX3 from activated neutrophils could contribute to protein plasma level elevation after ischemia, preceding gene-expression-dependent production. Murine models have recently provided a genetic demonstration of the regulatory role of PTX3 in AMI. PTX3-deficient mice showed increased heart damage, increased neutrophil infiltration in the ischemic area, a decreased number of small vessels, and increased apoptosis [25]. Given the conservation of PTX3 in evolution in terms of sequence, gene organization, and regulation, studies in mice could be informative about its in vivo functions in human pathology. It was therefore important to assess PTX3 expression in human cardiovascular diseases.
Here we report the expression of PTX3 in the human myocardial tissues of patients with AMI and infectious myocarditis by immunohistochemistry (IHC), demonstrating the presence of extracellular PTX3 within and around lesions and, in addition, in the cytoplasm of granulocytes, macrophages, endothelial cells and, more rarely, myocardiocytes.
Section snippets
Patients
Heart tissues from 50 patients (mean age, 54 years old; 38 males and 12 females) were retrospectively examined. Autopsies were performed at the Pathology Unit, L. Sacco Hospital (Milan, Italy) during a period of 10 years (1996–2005). Twenty-four cases had transmural AMI, 21 were HIV-positive patients with infectious myocarditis, and 5 died of cerebral events with no heart lesions.
PTX3 is not expressed in normal heart
PTX3 expression in normal heart was assessed by analyzing heart samples from five patients who died of cerebral events. In these samples, we did not find an expression of PTX3 by any type of cells. Similarly, we did not observe PTX3 immunostaining in normal heart areas from patients with AMI and infectious myocarditis.
PTX3 is expressed in the heart of AMI patients
We next analyzed PTX3 expression in AMI patients, divided according to the timing of ischemic lesions (Table 1). We found PTX3 immunostaining in all cases of this group. Fig. 1
Discussion
Despite widespread interest in the plasma evaluation of pentraxin levels in infectious diseases and ischemic heart lesions [23], [24], the tissue distribution of PTX3 protein in human cardiac samples has not been well characterized. In this study, using IHC, we assessed PTX3 expression in the heart tissues of patients with AMI at different time points after the ischemic event. In addition, we studied heart tissues from patients with infectious myocarditis and patients who died of noncardiac
Summary
This study characterized the expression of PTX3 in the heart tissues of patients with myocardial infarction (AMI) and infectious myocarditis, and in normal cardiac tissues, and indicates that it is locally produced during heart diseases. In particular, neutrophils are an early source of PTX3 in AMI and presumably in other inflammatory heart disorders. Subsequently, PTX3 is produced by macrophages, the endothelium, and, to a lesser extent, myocardiocytes, and is localized in the interstitium.
References (28)
- et al.
The acute phase response
Immunol Today
(1994) CRP after 2004
Mol Immunol
(2005)- et al.
PTX3 interacts with inter-alpha-trypsin inhibitor: implications for hyaluronan organization and cumulus oophorus expansion
J Biol Chem
(2007) - et al.
Multimer formation and ligand recognition by the long pentraxin PTX3. Similarities and differences with the short pentraxins C-reactive protein and serum amyloid P component
J Biol Chem
(1997) - et al.
The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells
Blood
(2000) - et al.
The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens
Blood
(2006) - et al.
Modified atherogenic lipoproteins induce expression of pentraxin-3 by human vascular smooth muscle cells
Atherosclerosis
(2004) - et al.
Pentraxin 3 is a novel marker for stent-induced inflammation and neointimal thickening
Atherosclerosis
(2008) - et al.
Prognostic value of pentraxin 3 in patients with chronic heart failure
Int J Cardiol
(2008) - et al.
Pentraxin 3, a new marker for vascular inflammation, predicts adverse clinical outcomes in patients with heart failure
Am Heart J
(2008)
Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites
Blood
Complexity and complementarity of outer membrane protein A recognition by cellular and humoral innate immunity receptors
Immunity
C-reactive protein: a critical update
J Clin Invest
Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility
Annu Rev Immunol
Cited by (50)
Pentraxin 3 regulates tyrosine kinase inhibitor-associated cardiomyocyte contraction and mitochondrial dysfunction via ERK/JNK signalling pathways
2023, Biomedicine and PharmacotherapyCitation Excerpt :The PTX3 gene, which encodes PTX3, is regulated by CCAAT/enhancer-binding protein delta (CEBPD), and PTX3 has been shown to support the protumour role of CEBPD.[9,11,12] Interestingly, elevated PTX3 expression is associated with several diseases, including HCC,[12] MI, increased severity of HF, and ventricular dysfunction.[13–16] For instance, our previous study revealed that PTX3 induced low-density lipoprotein (LDL) macropinocytosis by M1 macrophages in response to the p38mitogen-activated protein kinase (MAPK)/cAMP responsive element binding protein (CREB)/CEBPD signalling pathway, leading to an increase of atherosclerotic plaque formation.[17]
Update on the role of Pentraxin 3 in atherosclerosis and cardiovascular diseases
2017, Vascular PharmacologyCitation Excerpt :On the other hand, the release of PTX3 pre-stored in neutrophil granules exerts an early negative feedback on several platelet functions, including the formation of homo-/hetero-aggregate with neutrophils and mononuclear cells, the bind to fibrinogen, and the expression of P-selectin [34]. Other studies confirmed those findings and emphasized the role of neutrophils as early source of PTX3, whereas PTX3 release in the late stages is sustained by macrophages and ECs [132–134]. More recently, a whole blood transcriptomic analysis clearly identified PTX3 as component of the network orchestrating the inflammatory response triggered by ischemia/reperfusion injury [135,136].
Biological actions of pentraxins
2015, Vascular PharmacologyPentraxin 3 in Myocarditis: Proof-of-Principle Assessment as a Diagnostic and Prognostic Biomarker
2024, Journal of Cardiovascular Translational Research
This work was supported by Istituto Superiore di Sanità, MIUR, FIRB, Ministero della Salute; European Union Seventh Framework Program (TOLERAGE: HEALTH-F4-2008-202156); Cariplo (project Nobel); and European Research Council (HIIS).