Protease-activated receptor signaling in platelets activates cytosolic phospholipase A2α differently for cyclooxygenase-1 and 12-lipoxygenase catalysis.
| Autor: | Holinstat M; Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107, USA. michael.holinstat@jefferson.edu, Boutaud O, Apopa PL, Vesci J, Bala M, Oates JA, Hamm HE |
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| Jazyk: | angličtina |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2011 Feb; Vol. 31 (2), pp. 435-42. Date of Electronic Publication: 2010 Dec 02. |
| DOI: | 10.1161/ATVBAHA.110.219527 |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
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