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. CONCLUSIONS: These results are suggestive of EP4 receptor activation as a novel antithrombotic strategy.
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. CONCLUSIONS: These results are suggestive of EP4 receptor activation as a novel antithrombotic strategy.
Authors: Veronica H Flood; Abraham C Schlauderaff; Sandra L Haberichter; Tricia L Slobodianuk; Paula M Jacobi; Daniel B Bellissimo; Pamela A Christopherson; Kenneth D Friedman; Joan Cox Gill; Raymond G Hoffmann; Robert R Montgomery Journal: Blood Date: 2015-02-06 Impact factor: 22.113
Authors: Michael J Cima; Heejin Lee; Karen Daniel; Laura M Tanenbaum; Aikaterini Mantzavinou; Kevin C Spencer; Qunya Ong; Jay C Sy; John Santini; Carl M Schoellhammer; Daniel Blankschtein; Robert S Langer Journal: J Control Release Date: 2014-05-04 Impact factor: 9.776
Authors: Ryan R Hansen; Adam R Wufsus; Steven T Barton; Abimbola A Onasoga; Rebecca M Johnson-Paben; Keith B Neeves Journal: Ann Biomed Eng Date: 2012-09-22 Impact factor: 3.934
Authors: Sonia Philipose; Viktoria Konya; Mirjana Lazarevic; Lisa M Pasterk; Gunther Marsche; Sasa Frank; Bernhard A Peskar; Akos Heinemann; Rufina Schuligoi Journal: PLoS One Date: 2012-08-01 Impact factor: 3.240