Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis.

Holinstat M, Boutaud O, Apopa PL, Vesci J, Bala M, Oates JA, Hamm HE
Arterioscler Thromb Vasc Biol. 2011 31 (2): 435-42

PMID: 21127289 · PMCID: PMC3035574 · DOI:10.1161/ATVBAHA.110.219527

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.

MeSH Terms (21)

1-Butanol 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid Arachidonate 12-Lipoxygenase Arachidonic Acid Blood Platelets Calcium Chromones Cyclooxygenase 1 Cytosol Eicosanoids Enzyme Inhibitors Group IV Phospholipases A2 Humans In Vitro Techniques Morpholines p38 Mitogen-Activated Protein Kinases Propranolol Protein Kinase C Receptors, Proteinase-Activated Signal Transduction Thromboxane A2

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