In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 12 ( 2010-12), p. 2416-2423
Abstract:
Objective— Low concentrations of prostaglandin (PG) E 2 enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE 2 are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE 2 has been suggested to involve EP3 receptors. Here we analyzed the receptor usage relating to the inhibitory effect of PGE 2 . Methods and Results— Using flow cytometry, we found that human platelets expressed EP4 receptor protein. A selective EP4 agonist (ONO AE1-329) potently inhibited the platelet aggregation as induced by ADP or collagen. This effect could be completely reversed by an EP4 antagonist, but not by PGI 2 , PGD 2 , and thromboxane receptor antagonists or cyclooxygenase inhibition. Moreover, an EP4 antagonist enhanced the PGE 2 -induced stimulation of platelet aggregation, indicating a physiological antiaggregatory activity of EP4 receptors. The inhibitory effect of the EP4 agonist was accompanied by attenuated Ca 2+ flux, inhibition of glycoprotein IIb/IIIa, and downregulation of P-selectin. Most importantly, adhesion of platelets to fibrinogen under flow and in vitro thrombus formation were effectively prevented by the EP4 agonist. In this respect, the EP4 agonist synergized with acetylsalicylic acid. Conclusion— These results are suggestive of EP4 receptor activation as a novel antithrombotic strategy.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/ATVBAHA.110.216374
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2010
detail.hit.zdb_id:
1494427-3
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