2. Academic Validation
  3. Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions

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

  • Platelets. 2019;30(1):126-135. doi: 10.1080/09537104.2017.1406076.
Rachel A Rigg 1,  Laura D Healy 2,  Tiffany T Chu 1,  Anh T P Ngo 1,  Annachiara Mitrugno 1,  Jevgenia Zilberman-Rudenko 1,  Joseph E Aslan 3 4,  Monica T Hinds 1,  Lisa Dirling Vecchiarelli 5,  Terry K Morgan 5,  András Gruber 1 6,  Kayla J Temple 7 8,  Craig W Lindsley 7 8,  Matthew T Duvernay 7,  Heidi E Hamm 7,  Owen J T McCarty 1 2 6
Affiliations

Affiliations

  • 1 a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
  • 2 b Department of Cell, Developmental & Cancer Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
  • 3 d Department of Biochemistry and Molecular Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
  • 4 e Knight Cardiovascular Institute , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
  • 5 f Department of Pathology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
  • 6 c Division of Hematology & Medical Oncology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
  • 7 g Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , TN , USA.
  • 8 h Vanderbilt Center for Neuroscience Drug Discovery , Nashville , TN , USA.
PMID: 30560697 DOI: 10.1080/09537104.2017.1406076
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.

Keywords

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

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