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  • Title: Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis.
    Author: Holinstat M, Boutaud O, Apopa PL, Vesci J, Bala M, Oates JA, Hamm HE.
    Journal: Arterioscler Thromb Vasc Biol; 2011 Feb; 31(2):435-42. PubMed ID: 21127289.
    Abstract:
    OBJECTIVE: The rate-limiting step in the biosynthesis of thromboxane A(2) (TxA(2)) and 12-hydroxyeicosatetraenoic acid (12-HETE) by platelets is activation of cytosolic phospholipase A(2α) (cPLA(2α)), which releases arachidonic acid, which is the substrate for cyclooxygenase-1 (COX-1) and 12-lipoxygenase. We evaluated signaling via the human platelet thrombin receptors, protease-activated receptor (PAR) 1 and PAR4, to the activation of cPLA(2α), which provides a substrate for the biosynthesis of TxA(2) and 12-HETE. METHODS AND RESULTS: Stimulating washed human platelets resulted in delayed biosynthesis of 12-HETE, which continues after maximal formation of TxA(2) is completed, suggesting that 12-HETE is not formed by the same pool of arachidonic acid that provides a substrate to COX-1. PAR1-induced formation of TxA(2) was inhibited by the phosphatidylinositol kinase inhibitor LY294002, whereas this inhibitor did not block 12-HETE biosynthesis. Both 1-butanol and propranolol also blocked TxA(2) biosynthesis but did not inhibit 12-HETE formation. CONCLUSIONS: The concerted evidence indicates that the platelet thrombin receptors signal activation of cPLA(2α) coupled to COX-1 by a pathway different from that signaling activation of the cPLA(2α) coupled to 12-lipoxygenase.
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