TY - JOUR
T1 - Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions
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 E.
AU - Hinds, Monica T.
AU - Vecchiarelli, Lisa Dirling
AU - Morgan, Terry K.
AU - Gruber, András
AU - Temple, Kayla J.
AU - Lindsley, Craig W.
AU - Duvernay, Matthew T.
AU - Hamm, Heidi E.
AU - McCarty, Owen J.T.
N1 - Publisher Copyright:
© 2017, © 2017 Taylor & Francis.
PY - 2019/1/2
Y1 - 2019/1/2
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.
AB - 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.
KW - PAR4
KW - granulocytes
KW - platelet activation
KW - platelet dense granule release
KW - platelet-leukocyte interactions
KW - protease-activated receptor 4
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U2 - 10.1080/09537104.2017.1406076
DO - 10.1080/09537104.2017.1406076
M3 - Article
C2 - 30560697
AN - SCOPUS:85058711814
SN - 0953-7104
VL - 30
SP - 126
EP - 135
JO - Platelets
JF - Platelets
IS - 1
ER -