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

Autor: Rigg RA; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Healy LD; b Department of Cell, Developmental & Cancer Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Chu TT; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Ngo ATP; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Mitrugno A; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Zilberman-Rudenko J; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Aslan JE; d Department of Biochemistry and Molecular Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.; e Knight Cardiovascular Institute , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Hinds MT; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Vecchiarelli LD; f Department of Pathology , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Morgan TK; f Department of Pathology , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Gruber A; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA.; c Division of Hematology & Medical Oncology , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Temple KJ; g Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , TN , USA.; h Vanderbilt Center for Neuroscience Drug Discovery , Nashville , TN , USA., Lindsley CW; g Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , TN , USA.; h Vanderbilt Center for Neuroscience Drug Discovery , Nashville , TN , USA., Duvernay MT; g Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , TN , USA., Hamm HE; g Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , TN , USA., McCarty OJT; a Department of Biomedical Engineering , School of Medicine, Oregon Health & Science University , Portland , OR , USA.; b Department of Cell, Developmental & Cancer Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.; c Division of Hematology & Medical Oncology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.
Jazyk: angličtina
Zdroj: Platelets [Platelets] 2019; Vol. 30 (1), pp. 126-135. Date of Electronic Publication: 2018 Dec 18.
DOI: 10.1080/09537104.2017.1406076
Abstrakt: 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: MEDLINE
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