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

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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Leukocytes
Blood Platelets
Cathepsin G
Fibrinolysin
Platelet Activation
Thrombin
protease-activated receptor 4
Thrombosis
Proteinase-Activated Receptors
P-Selectin
Serine Proteases
Pathologic Processes
Hemostasis
Pharmacology
Peptides

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. / Rigg, Rachel A.; Healy, Laura D.; Chu, Tiffany T.; Ngo, Anh T.P.; Mitrugno, Annachiara; Zilberman-Rudenko, Jevgenia; Aslan, Joseph; Hinds, Monica; Vecchiarelli, Lisa Dirling; Morgan, Terry; Gruber, Andras; Temple, Kayla J.; Lindsley, Craig W.; Duvernay, Matthew T.; Hamm, Heidi E.; McCarty, Owen.

In: Platelets, 01.01.2018.

Research output: Contribution to journalArticle

Rigg, RA, Healy, LD, Chu, TT, Ngo, ATP, Mitrugno, A, Zilberman-Rudenko, J, Aslan, J, Hinds, M, Vecchiarelli, LD, Morgan, T, Gruber, A, Temple, KJ, Lindsley, CW, Duvernay, MT, Hamm, HE & McCarty, O 2018, 'Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions', Platelets. https://doi.org/10.1080/09537104.2017.1406076
Rigg, Rachel A. ; Healy, Laura D. ; Chu, Tiffany T. ; Ngo, Anh T.P. ; Mitrugno, Annachiara ; Zilberman-Rudenko, Jevgenia ; Aslan, Joseph ; Hinds, Monica ; Vecchiarelli, Lisa Dirling ; Morgan, Terry ; Gruber, Andras ; Temple, Kayla J. ; Lindsley, Craig W. ; Duvernay, Matthew T. ; Hamm, Heidi E. ; McCarty, Owen. / Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. In: Platelets. 2018.
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AU - Rigg, Rachel A.

AU - Healy, Laura D.

AU - Chu, Tiffany T.

AU - Ngo, Anh T.P.

AU - Mitrugno, Annachiara

AU - Zilberman-Rudenko, Jevgenia

AU - Aslan, Joseph

AU - Hinds, Monica

AU - Vecchiarelli, Lisa Dirling

AU - Morgan, Terry

AU - Gruber, Andras

AU - Temple, Kayla J.

AU - Lindsley, Craig W.

AU - Duvernay, Matthew T.

AU - Hamm, Heidi E.

AU - McCarty, Owen

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N2 - 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.

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