The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: A potential mechanism for thrombosis in eosinophilic inflammatory states

Hematology, Oncology, and Transplantation Section, Department of Medicine, and the Vascular Biology Center, University of Minnesota, Minneapolis, USA.
Blood (Impact Factor: 10.45). 02/2006; 107(2):558-65. DOI: 10.1182/blood-2005-05-2152
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In vivo, bromide (Br(-)), nitrite (NO(2)(-)), and thiocyanate (SCN(-)) compete for oxidation by eosinophil peroxidase (EPO) and H(2)O(2), yielding, respectively, HOBr, NO(2)., and HOSCN. We have recently shown that SCN(-) is the strongly preferred substrate for EPO in vivo and that HOSCN, in contrast with other EPO-generated oxidants and HOCl, is a relatively weak, cell-permeant, sulfhydryl (SH)-reactive oxidant. We here show that HOSCN is a uniquely potent (up to 100-fold) phagocyte oxidant inducer of tissue factor (TF) activity in human umbilical vein endothelial cells (HUVECs). This induction is attributable to transcriptional up-regulation of TF gene expression dependent upon both activation of the p65/c-Rel TF-kappaB transcription factor and activity of the ERK1/2 kinase pathway upstream of Egr-1 and was markedly further enhanced in the presence of wortmannin, an inhibitor of the PI3 kinase/Akt pathway. HOSCN also markedly activates the proinflammatory p65/p50 NF-kappaB pathway. Based on these findings we hypothesize that HOSCN generated by adherent and infiltrating eosinophils may provoke the development of a prothrombotic and proinflammatory endothelial/endocardial phenotype that promotes the pronounced thrombotic diathesis characteristic of the hypereosinophilic syndrome.

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Available from: Nigel S Key, Mar 22, 2015
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    • "The main function of myeloperoxidase is to destroy phagocytosed microorganisms by generating highly reactive hipochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) within the phagosome. The generation of these reactive species is dependent on the presence of H 2 O 2 and a halide, such as chlorine or cyanide [2] [3]. "
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    Turkish Journal of Biochemistry 09/2015; 40(5):410-416. DOI:10.1515/tjb-2015-0035
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    • "Eosinophils are known to play an important role in endothelial dysfunction, inflammation, and thrombosis (8,9). Additionally, vascular anomalies, such as aneurysms, have been noted in patients with hypereosinophilic syndromes (10,11). "
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    Clinics (São Paulo, Brazil) 05/2014; 69(5):323-6. DOI:10.6061/clinics/2014(05)05 · 1.19 Impact Factor
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    • "MBP can inhibit the anticoagulant activities of the endothelial membrane by binding to thrombomodulin. 11,12 Moreover, hypothiocyanous acid (HOSCN), the predominant oxidant product of EPO, has been shown to stimulate tissue factor expression, thus promoting thrombosis.13 "
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    Allergy, asthma & immunology research 05/2012; 4(3):161-4. DOI:10.4168/aair.2012.4.3.161 · 2.43 Impact Factor
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