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Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor

Academic Article
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Overview

authors

  • Ahamed, J.
  • Belting, M.
  • Ruf, Wolfram

publication date

  • March 2005

journal

  • Blood  Journal

abstract

  • Tissue factor (TF) triggers upstream coagulation signaling via the activation of protease-activated receptors (PARs) of relevance for inflammation and angiogenesis. TF pathway inhibitor 1 (TFPI-1) is the physiologic inhibitor of TF-initiated coagulation, but its role in regulating TF signaling is poorly understood. Here, we demonstrate that endogenous, endothelial cell-expressed TFPI-1 controls TF-mediated signaling through PARs. In endothelial cells transduced with TF to mimic exacerbated TF expression in vascular cells, TF-VIIa-Xa ternary complex-dependent activation of PAR1 remained intact when TF-mediated Xa generation was blocked with 2.5 to 5 nM recombinant TFPI-1 (rTFPI-1). Concordantly, inhibition of signaling in PAR1-expressing Chinese hamster ovary (CHO) cells required about 30-fold higher rTFPI-1 concentrations than necessary for anticoagulation. Studies with proteoglycan-deficient CHO cells document a crucial role of accessory receptors in supporting the anticoagulant and antisignaling activities of rTFPI-1. Coexpression of PAR2 with TF enhanced rTFPI-mediated inhibition of TF-VIIa-Xa-mediated PAR1 signaling, suggesting an unexpected role of PAR2 in the inhibitory control of TF signaling. These experiments are of potential significance for the limited therapeutic benefit of rTFPI-1 in systemic inflammation and recommend caution in using anticoagulant potency as a measure to predict how efficacious TF-directed inhibitors block cell signaling during initiation of coagulation.

subject areas

  • Animals
  • Blood Coagulation
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Factor VIIa
  • Factor Xa
  • Humans
  • Inflammation
  • Lipoproteins
  • Multienzyme Complexes
  • Proteoglycans
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Signal Transduction
  • Thrombin
  • Thromboplastin
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Identity

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2004-09-3422

PubMed ID

  • 15550483
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Additional Document Info

start page

  • 2384

end page

  • 2391

volume

  • 105

issue

  • 6

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