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Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation

Reinhardt, Christoph and von Brühl, Marie Luise and Manukyan, Davit and Grahl, Lenka and Lorenz, Michael and Altmann, Berid and Dlugai, Silke and Hess, Sonja and Konrad, Aldiko and Orschiedt, Lena and Mackman, Nigel and Ruddock, Lloyd and Massberg, Steffen and Engelmann, Bernd (2008) Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. Journal of Clinical Investigation, 118 (3). pp. 1110-1123. ISSN 0021-9738.

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The activation of initiator protein tissue factor (TF) is likely to be a crucial step in the blood coagulation process, which leads to fibrin formation. The stimuli responsible for inducing TF activation are largely undefined. Here we show that the oxidoreductase protein disulfide isomerase (PDI) directly promotes TF-dependent fibrin production during thrombus formation in vivo. After endothelial denudation of mouse carotid arteries, PDI was released at the injury site from adherent platelets and disrupted vessel wall cells. Inhibition of PDI decreased TF-triggered fibrin formation in different in vivo murine models of thrombus formation, as determined by intravital fluorescence microscopy. PDI infusion increased — and, under conditions of decreased platelet adhesion, PDI inhibition reduced — fibrin generation at the injury site, indicating that PDI can directly initiate blood coagulation. In vitro, human platelet–secreted PDI contributed to the activation of cryptic TF on microvesicles (microparticles). Mass spectrometry analyses indicated that part of the extracellular cysteine 209 of TF was constitutively glutathionylated. Mixed disulfide formation contributed to maintaining TF in a state of low functionality. We propose that reduced PDI activates TF by isomerization of a mixed disulfide and a free thiol to an intramolecular disulfide. Our findings suggest that disulfide isomerases can act as injury response signals that trigger the activation of fibrin formation following vessel injury.

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Hess, Sonja0000-0002-5904-9816
Additional Information:© 2008 by the American Society for Clinical Investigation. Received for publication April 11, 2007, and accepted in revised form December 19, 2007. First published February 14, 2008. We thank Hans-Dieter Söling, Manuel Than, Rein Aasland, and Klaus T. Preissner for discussions and helpful suggestions. We thank Elisabeth Kremmer, Viktor Magdolen, Sybille Albrecht, and Thomas Luther for providing substances. C. Reinhardt, D. Manukyan, and B. Altmann have been participants of the DFG-Graduiertenkolleg “Vaskuläre Biologie in der Medizin”. L. Grahl was supported by DFG-Forschergruppe “Prävention des Ischämie-Reperfusionsschadens”. S. Massberg is a Heisenberg fellow of the DFG. This work was supported by grants from the DFG and Stiftung für Pathobiochemie und Molekulare Diagnostik (to B. Engelmann and S. Massberg), the Intramural Research Program of the NIH NIDDK, and the Betty and Gordon Moore Foundation (to S. Hess). Mass spectrometry experiments were conducted at the Proteomics and Mass Spectrometry Facility of the NIDDK. Conflict of interest: The authors have declared that no conflict of interest exists. Christoph Reinhardt and Marie-Luise von Brühl contributed equally to this work.
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Deposited On:21 Mar 2008
Last Modified:04 Dec 2019 18:20

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