Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions
| Autor: | Lisa Dirling Vecchiarelli, Owen J. T. McCarty, Annachiara Mitrugno, Rachel A. Rigg, Heidi E. Hamm, Matthew T. Duvernay, Anh T. P. Ngo, Jevgenia Zilberman-Rudenko, Andras Gruber, Terry K. Morgan, Craig W. Lindsley, Monica T. Hinds, Laura D. Healy, Tiffany T. Chu, Joseph E. Aslan, Kayla J. Temple |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proteases Plasmin Hematology General Medicine 030204 cardiovascular system & hematology Cathepsin G Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Thrombin chemistry Hemostasis medicine Platelet Platelet activation Receptor medicine.drug |
| DOI: | 10.6084/m9.figshare.7479287.v1 |
| Popis: | Human platelets express two protease-activated receptors (PARs), PAR1 (F2R) and PAR4 (F2RL3), which are activated by a number of serine proteases that are generated during pathological events and cause platelet activation. Recent interest has focused on PAR4 as a therapeutic target, given PAR4 seems to promote experimental thrombosis and procoagulant microparticle formation, without a broadly apparent role in hemostasis. However, it is not yet known whether PAR4 activity plays a role in platelet-leukocyte interactions, which are thought to contribute to both thrombosis and acute or chronic thrombo-inflammatory processes. We sought to determine whether PAR4 activity contributes to granule secretion from activated platelets and platelet-leukocyte interactions. We performed in vitro and ex vivo studies of platelet granule release and platelet-leukocyte interactions in the presence of PAR4 agonists including PAR4 activating peptide, thrombin, cathepsin G, and plasmin in combination with small-molecule PAR4 antagonists. Activation of human platelets with thrombin, cathepsin G, or plasmin potentiated platelet dense granule secretion that was specifically impaired by PAR4 inhibitors. Platelet-leukocyte interactions and platelet P-selectin exposure the following stimulation with PAR4 agonists were also impaired by activated PAR4 inhibition in either a purified system or in whole blood. These results indicate PAR4-specific promotion of platelet granule release and platelet-leukocyte aggregate formation and suggest that pharmacological control of PAR4 activity could potentially attenuate platelet granule release or platelet-leukocyte interaction-mediated pathological processes. |
| Databáze: | OpenAIRE |
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