Endothelial PAI-1 (Plasminogen Activator Inhibitor-1) Blocks the Intrinsic Pathway of Coagulation, Inducing the Clearance and Degradation of FXIa (Activated Factor XI)
| Autor: | David Gailani, Cristina Puy, Andras Gruber, Matthew W. Hagen, Anh T. P. Ngo, Owen J. T. McCarty, Monica T. Hinds, Jiaqing Pang, Florea Lupu, Ravi S. Keshari |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Endothelium 030204 cardiovascular system & hematology Pharmacology Factor XIa Article Fibrin 03 medical and health sciences chemistry.chemical_compound Papio ursinus 0302 clinical medicine Thrombin Plasminogen Activator Inhibitor 1 medicine Animals Humans Platelet activation Blood Coagulation biology Chemistry Endothelial Cells Kallikrein Blot 030104 developmental biology medicine.anatomical_structure Plasminogen activator inhibitor-1 biology.protein Cardiology and Cardiovascular Medicine Plasminogen activator medicine.drug |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.119.312619 |
| Popis: | Objective— Activation of coagulation FXI (factor XI) by FXIIa (activated factor XII) is a prothrombotic process. The endothelium is known to play an antithrombotic role by limiting thrombin generation and platelet activation. It is unknown whether the antithrombotic role of the endothelium includes sequestration of FXIa (activated factor XI) activity. This study aims to determine the role of endothelial cells (ECs) in the regulation of the intrinsic pathway of coagulation. Approach and Results— Using a chromogenic assay, we observed that human umbilical veins ECs selectively blocked FXIa yet supported kallikrein and FXIIa activity. Western blotting and mass spectrometry analyses revealed that FXIa formed a complex with endothelial PAI-1 (plasminogen activator inhibitor-1). Blocking endothelial PAI-1 increased the cleavage of a chromogenic substrate by FXIa and the capacity of FXIa to promote fibrin formation in plasma. Western blot and immunofluorescence analyses showed that FXIa–PAI-1 complexes were either released into the media or trafficked to the early and late endosomes and lysosomes of ECs. When baboons were challenged with Staphylococcus aureus to induce a prothrombotic phenotype, an increase in circulating FXIa–PAI-1 complex levels was detected by ELISA within 2 to 8 hours postchallenge. Conclusions— PAI-1 forms a complex with FXIa on ECs, blocking its activity and inducing the clearance and degradation of FXIa. Circulating FXIa–PAI-1 complexes were detected in a baboon model of S. aureus sepsis. Although ECs support kallikrein and FXIIa activity, inhibition of FXIa by ECs may promote the clearance of intravascular FXIa. Visual Overview— An online visual overview is available for this article. |
| Databáze: | OpenAIRE |
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