Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions |
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Authors: | Rachel A. Rigg Laura D. Healy Tiffany T. Chu Anh T. P. Ngo Annachiara Mitrugno Jevgenia Zilberman-Rudenko |
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Affiliation: | 1. Department of Biomedical Engineering, School of Medicine, Oregon Health &2. Science University, Portland, OR, USA;3. Department of Cell, Developmental &4. Cancer Biology, School of Medicine, Oregon Health & |
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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. |
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Keywords: | PAR4 platelet-leukocyte interactions platelet dense granule release platelet activation protease-activated receptor 4 granulocytes |
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