Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1
(2005) In Blood 105(6). p.2384-2391- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1132927
- author
- Ahamed, Jasimuddin ; Belting, Mattias LU and Ruf, Wolfram
- publishing date
- 2005
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood
- volume
- 105
- issue
- 6
- pages
- 2384 - 2391
- publisher
- American Society of Hematology
- external identifiers
-
- pmid:15550483
- scopus:15244349532
- pmid:15550483
- ISSN
- 1528-0020
- DOI
- 10.1182/blood-2004-09-3422
- language
- English
- LU publication?
- no
- id
- e961e465-0b03-4894-84a4-7d67e01d65ed (old id 1132927)
- date added to LUP
- 2016-04-01 12:27:57
- date last changed
- 2022-04-21 07:48:46
@article{e961e465-0b03-4894-84a4-7d67e01d65ed,
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.}},
author = {{Ahamed, Jasimuddin and Belting, Mattias and Ruf, Wolfram}},
issn = {{1528-0020}},
language = {{eng}},
number = {{6}},
pages = {{2384--2391}},
publisher = {{American Society of Hematology}},
series = {{Blood}},
title = {{Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1}},
url = {{http://dx.doi.org/10.1182/blood-2004-09-3422}},
doi = {{10.1182/blood-2004-09-3422}},
volume = {{105}},
year = {{2005}},
}