Article

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
Source: PubMed

ABSTRACT

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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    • "In agreement, the GR (glutathione reductase )/GPx (glutathione peroxidase) ratio also increased (Fig. 1C), showing enhanced GSH-linked activity with a concomitant reduced peroxidative state. Therefore, it is feasible that neopterin increases the cell's resistance to oxidative stress by activating transcription factors related to ARE (antioxidant response element) genes, by inducing electrophilic stress as previously proposed (Cirillo et al., 2006) or by direct interaction with the DNA as demonstrated for tetrahydrobiopterin, another pterin member family (Kure et al., 1999; Rodrigues et al., 2012). Although more studies are necessary to characterize neopterin citoprotective potential, we believe that the metabolite has a specific role, greater than just being an inert marker of immune system activation in the central nervous system. "

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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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    • "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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