Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation
Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation
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DOI：
10.1172/jci10881
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发表时间：
2001-03-01
影响因子：
15.9
通讯作者：
Koller, BH
中科院分区：
文献类型：
--
作者：
Fabre, JE;Nguyen, M;Koller, BH
花生四烯酸代谢物（称为类花生酸），特别是源自考克斯-1和考克斯-2途径的那些（称为前列腺素）在血小板稳态中的重要性早已被认识到。血栓烷是有效的激动剂，而前列环素是血小板聚集的抑制剂。相比之下，前列腺素E-2（PGE（2））对血小板聚集的影响因其浓度而异。低浓度的PGE（2）可增强血小板聚集，而高浓度的PGE（2）可抑制血小板聚集。PGE（2）的这种双重作用的机制尚不清楚。本研究表明，在四种PGE（2）受体（EP 1-EP 4）中，EP 3的激活足以介导低浓度PGE（2）的促聚集作用。相比之下，前列环素受体（IP）介导较高浓度PGE（2）的抑制作用。此外，这两种受体EP 3和IP的相对活化调节cAMP的细胞内水平，并以这种方式调节血小板对聚集剂的反应。与这些发现相一致，在静脉炎症模型中EP 3受体的缺失可以防止血管内凝块的形成。我们的研究结果表明，在炎症过程中局部产生的PGE（2）可以调节随后的血小板反应。
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 E-2 (PGE(2)) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE(2) enhance platelet aggregation, whereas high PGE(2) levels inhibit aggregation. The mechanism for this dual action of PGE(2) is not clear. This study shows that among the four PGE(2) receptors (EP1-EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE(2) concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE(2) 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 PGE(2) during an inflammatory process can modulate ensuing platelet responses.