Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP3

Article

关键词: HAMSTER OVARY CELLS;    PROSTANOID RECEPTORS;    THROMBOXANE A(2);    PLATELETS;    MOUSE;    ENDOPEROXIDES;    AGGREGATION;    MULTIPLICITY;    PROSTACYCLIN;    POTENTIATION;   

DOI  :  10.1161/hc3601.094003

来源: SCIE

【 摘 要 】

Background-Among the prostanoids, thromboxane (TX) A(2) is a potent stimulator of platelets, whereas prostaglandin (PG) I-2 inhibits their activation. The roles of PGE(2) in the regulation of platelet function have not been established, however, and the contribution of PGE(2) in hemostasis and thromboembolism is poorly understood. The present study was intended to clarify these roles of PGE(2) by using mice lacking the PGE(2) receptor subtype 3 (EP3-/- mice). Methods and Results-Expression of mRNAs for EP3 in murine platelets was confirmed by quantitative reverse transcription-polymerase chain reaction. PGE(2) and AE-248, a selective EP3 agonist, showed concentration-dependent potentiation of platelet aggregation induced by U46619, a TXA(2) receptor agonist, although PGE2 alone could not induce aggregation. PGE(2) and AE-248 increased cytosolic calcium ion concentration ([Ca2+](i)), and AE-248 inhibited the forskolin-induced increase in cytosolic cAMP concentration ([cAMP]i), suggesting G(i) coupling of EP3. The potentiating effects of PGE(2) and AE-248 on platelet aggregation along with their effects on [Ca2+](i) and [cAMP](i) were absent in EP3-/- mice. In vivo, the bleeding time was significantly prolonged in EP3-/- mice. Moreover, when mice were challenged intravenously with arachidonic acid, mortality and thrombus formation in the lung were significantly reduced in EP3-/- mice. Conclusions-PGE(2) potentiated platelet aggregation induced by U46619 via EP3 by increasing [Ca2+](i), decreasing [cAMP](i), or both. This potentiating action of PGE(2) via EP3 is essential in mediating both physiological and pathological effects of PGE(2) in vivo.

【 授权许可】

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