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Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation
Jean-Etienne Fabre, … , Thomas M. Coffman, Beverly H. Koller
Jean-Etienne Fabre, … , Thomas M. Coffman, Beverly H. Koller
Published March 1, 2001
Citation Information: J Clin Invest. 2001;107(5):603-610. https://doi.org/10.1172/JCI10881.
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Article

Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation

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Abstract

The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized. Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1–EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE2 during an inflammatory process can modulate ensuing platelet responses.

Authors

Jean-Etienne Fabre, MyTrang Nguyen, Krairek Athirakul, Kenneth Coggins, John D. McNeish, Sandra Austin, Leslie K. Parise, Garret A. FitzGerald, Thomas M. Coffman, Beverly H. Koller

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Figure 2

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The PGE2-induced potentiation of aggregation is mediated by the EP3 rece...
The PGE2-induced potentiation of aggregation is mediated by the EP3 receptor. Comparison of PGE2 (10–7 M) mediated potentiation of aggregation induced by U46619 (1 μM; indicated by the letter “U”) treatment of wild-type platelets (WT) and platelets deficient for each of the prostaglandin receptors. PGE2-induced potentiation is observed in all the samples, with the exception of those lacking the EP3 receptor. Bars = 1 minute. Similar results were obtained on three consecutive experiments, and representative traces are shown. The maximal aggregation induced by PGE2 treatment of EP receptor-deficient platelets in each experiment was calculated, and the mean was compared with similarly treated wild-type platelets. A significant difference (unpaired t test; P < 0.01) was observed only on comparison of the EP3-deficient platelet with wild-type controls.

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