Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions

Rachel A. Rigg, Laura D. Healy, Tiffany T. Chu, Anh T.P. Ngo, Annachiara Mitrugno, Jevgenia Zilberman-Rudenko, Joseph Aslan, Monica Hinds, Lisa Dirling Vecchiarelli, Terry Morgan, Andras Gruber, Kayla J. Temple, Craig W. Lindsley, Matthew T. Duvernay, Heidi E. Hamm, Owen McCarty

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalPlatelets
DOIs
StateAccepted/In press - Jan 1 2018

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Keywords

  • granulocytes
  • PAR4
  • platelet activation
  • platelet dense granule release
  • platelet-leukocyte interactions
  • protease-activated receptor 4

ASJC Scopus subject areas

  • Hematology

Cite this

Rigg, R. A., Healy, L. D., Chu, T. T., Ngo, A. T. P., Mitrugno, A., Zilberman-Rudenko, J., Aslan, J., Hinds, M., Vecchiarelli, L. D., Morgan, T., Gruber, A., Temple, K. J., Lindsley, C. W., Duvernay, M. T., Hamm, H. E., & McCarty, O. (Accepted/In press). Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. Platelets. https://doi.org/10.1080/09537104.2017.1406076