Neopterin induces pro-atherothrombotic phenotype in human coronary endothelial cells

Division of Cardiology, University of Naples 'Federico II', Naples, Italy.
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 11/2006; 4(10):2248-55. DOI: 10.1111/j.1538-7836.2006.02125.x
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Inflammation plays a pivotal role in atherothrombosis. Recent data indicate that serum levels of neopterin, a marker of inflammation and immune modulator secreted by monocytes/macrophages, are elevated in patients with acute coronary syndromes and seem to be a prognostic marker for major cardiovascular events. The aim of the present study was to determine whether neopterin might affect the thrombotic and atherosclerotic characteristics of human coronary artery endothelial cells (HCAECs).
In HCAECs, neopterin induced TF-mRNA transcription as demonstrated by real time polymerase chain reaction and expression of functionally active tissue factor (TF) as demonstrated by procoagulant activity assay, and of cellular adhesion molecules (CAMs) as demonstrated by FACS analysis, in a dose-dependent fashion. These neopterin effects were prevented by lovastatin, a HMG-CoA reductase inhibitor. Neopterin-induced TF and CAMs expression was mediated by oxygen free radicals through the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by suppression of CAMs and TF expression by superoxide dismutase and by NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium.
These data indicate that neopterin exerts direct effects on HCAECs by promoting CAMs and TF expression and support the hypothesis that neopterin, besides representing a marker of inflammation, might be an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation.

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    • "Chemiluminescence experiments revealed that neopterin increases effects of reactive compounds such as H 2 O 2 , OCl − , chloramine, and ONOO − , whereas is sister compound 7,8-dihydroneopterin can act as a scavenger (Weiss et al., 1993). Cirillo et al. (2006) and Hofmann et al. (1992) reported that neopterin is able to induce the translocation of NF-κB in human endothelial cells and vascular smooth muscle cells. Aqueous extracts of cacao were found to significantly suppress tryptophan breakdown and neopterin formation in a dosedependent manner in vitro (Jenny et al., 2009). "
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    ABSTRACT: Anti-inflammatory properties of cacao, fruits of Theobroma cacao L. (Sterculiaceae), are well documented, and therapeutic applications are described for gastrointestinal, nervous and cardiovascular abnormalities. Most, if not all of these disease conditions involve inflammation or immune activation processes. The pro-inflammatory cytokine interferon-γ (IFN-γ) and related biochemical pathways like tryptophan breakdown by indoleamine 2,3-dioxygenase (IDO) and neopterin formation are deeply involved in their pathogenesis. Neopterin concentrations and the kynurenine to tryptophan ratio (Kyn/Trp, an estimate of IDO activity) are elevated in a significant proportion of patients with virus infections, cancer, autoimmune syndrome, neurodegeneration and coronary artery disease. Moreover, higher neopterin and Kyn/Trp concentrations are indicative for poor prognosis. When investigating the effect of aqueous or ethanolic extracts of cacao on IFN-γ, neopterin and Kyn/Trp concentrations in mitogen-stimulated human peripheral blood mononuclear cells, breakdown of tryptophan by IDO and formation of neopterin and IFN-γ were dose-dependently suppressed. The effects observed in the cell-based assays are associated with the antioxidant activity of the cacao extracts as determined by the cell-free oxygen radical absorption capacity (ORAC) assay. The influence of cacao extracts on IDO activity could be of particular relevance for some of the beneficial health effects ascribed to cacao: tryptophan breakdown by IDO is strongly involved in immunoregulation, and the diminished availability of tryptophan limits the biosynthesis of neurotransmitter serotonin. The inhibition of tryptophan breakdown by cacao constituents could thus be relevant not only for immune system restoration in patients, but also contribute to mood elevation and thereby improve quality of life. However, the available data thus far are merely in vitro only and future studies need to be investigated.
    Frontiers in Pharmacology 12/2013; 4:154. DOI:10.3389/fphar.2013.00154 · 3.80 Impact Factor
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    • "Neopterin and CRP levels are elevated in patients with vascular disease, and relate to a higher risk of ischemic events (van Haelst et al., 2003). Furthermore, neopterin may itself induce endothelial dysfunction with increased expression of adhesion molecules as a consequence (Cirillo et al., 2006). We hypothesized that patients with CSVD have higher levels of neopterin, CRP, and soluble adhesion molecules, than patients without. "
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    ABSTRACT: Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD.
    Neurobiology of aging 05/2011; 33(8):1800-6. DOI:10.1016/j.neurobiolaging.2011.04.008 · 5.01 Impact Factor
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    • "In fact, it has been demonstrated that these mediators might exert their effects by inducing TF expression . Specifically, inflammatory markers such as C- Reactive Protein or neopterin as well as smoke-derivative substances might play an important role in acute coronary syndromes since it has been demonstrated that they are active partaker in triggering coronary TF-mediated coagulation [15] [45] [46]. In addition, molecules involved in pathophysiology of other cardiovascular co-morbidity such as urotensin II or angiotensin have been associated with TF expression to explain their mechanism of action [13] [47]. "
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    ABSTRACT: Blood coagulation is a complex biological mechanism aimed to avoid bleeding in which a highly regulated and coordinated interplay of specific proteins and cellular components respond quickly to a vascular injury. However, when this mechanisms occurs in the coronary circulation, it has not a “protective” effect, but rather, it plays a pivotal role in determining acute coronary syndromes. Coagulation recognizes Tissue Factor (TF), the main physiological initiator of the extrinsic coagulation pathway, as its starter. Since TF:VIIa complex is the critical point of the blood coagulation cascade, it is a pharmacological attractive issue for the development of agents with anti thrombotic properties that can exert their activity by inhibiting complex formation and/or its catalytic activity. In fact, it is intuitive that an antithrombotic agent able to inhibit this initial step of the coagulation pathway has several theoretical, extremely important, advantages if compared with drugs active downstream the coagulation pathway, such as FXa or thrombin. The present report gives a brief overview of TF pathophysiology, highlighting the most recent advances in the field of inhibitors of the complex TF/VIIa potentially useful in cardiovascular disease.
    Current Cardiology Reviews 11/2010; 6(4):325-32. DOI:10.2174/157340310793566190
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