Premium
Thrombin‐mediated thromboxane and 12‐HETE formation in human platelets is differentially regulated through PAR1 and PAR4
Author(s) -
Holinstat Michael,
Boutaud Olivier,
Hudson W. James,
Colowick Nancy,
Young Summer,
Oates John A.,
Hamm Heidi E.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.524.9
Subject(s) - platelet , platelet activation , thromboxane , thrombin , thromboxane a2 , chemistry , thrombus , microbiology and biotechnology , thromboxane a synthase , signal transduction , pharmacology , medicine , biochemistry , biology
Thrombin‐regulated platelet activation mediates a diverse range of vascular effects which may result in thrombus formation and stroke. Thromboxane (TxB 2 ) is thought to play a crucial role in the reinforcement of platelet activation following thrombin activation via TxB 2 formation in the platelet. We demonstrate that PAR1 and PAR4 work synergistically but through unique signaling pathways following activation in order to generate both TxB 2 as well as 12‐HETE. To investigate the signaling differences, we examined multiple biochemical and physiological steps involved in platelet activation including Rap1, aggregation, Ca 2+ mobilization and formation of 12‐HETE and TxB 2 . Inhibition of PIP 2 and PIP 3 significantly altered PAR1‐, but not PAR4‐mediated platelet aggregation and resulted in inhibition of TxB 2 , but not 12‐HETE. Additionally, the time course for PAR1‐mediated TxB 2 formation was faster compared to PAR4. Inhibiting PAR4 activation with YD3 only partially blocked thrombin‐mediated effects confirming the synergistic involvement of both PAR1 and PAR4 in this process. A better understanding of regulation of platelet function through PAR signaling pathways is crucial to developing a better class of anti‐platelet therapies with a lower profile for bleeding as a side effect. This study was supported in part by grants P50 HL081009 (to H.E.H.) and R00 HL089457 (to M.H.) from National Institutes of Health.