Audoly L P, Rocca B, Fabre J E, Koller B H, Thomas D, Loeb A L, Coffman T M, FitzGerald G A
Duke University and Durham Veterans Affairs Medical Centers, Durham, NC, USA.
Circulation. 2000 Jun 20;101(24):2833-40. doi: 10.1161/01.cir.101.24.2833.
Isoprostanes (iPs) are free radical-catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. Several iPs exert biological effects in vitro and may contribute to the functional consequences of oxidant stress. For example, iPF(2alpha)-III (8-iso PGF(2alpha)) and iPE(2)-III modulate platelet function and vascular tone. Although these effects are blocked by antagonists of the receptor (TP) for the cyclooxygenase product thromboxane A(2), it has been speculated that the iPs may activate a receptor related to, but distinct from, the TP.
Transgenic mice (TPOEs) were generated in which the TP-beta isoform was under the control of the preproendothelin promoter. They overexpressed TP-beta in the vasculature but not in platelets and exhibited an exaggerated pressor response to infused iPF(2alpha)-III compared with wild-type mice. This was blocked by TP antagonism. The platelet response to the iP was unaltered in TPOEs compared with wild-type mice. By contrast, both the pressor response to iPF(2alpha)-III and its effects on platelet function were abolished in mice lacking the TP gene. This was also true of the effects of infused iPE(2)-III on mean arterial pressure and platelet aggregation.
Both iPF(2alpha)-III and iPE(2)-III exert their effects on platelet function and vascular tone in vivo by acting as incidental ligands at membrane TPs rather than via a distinct iP receptor. Activation of TPs by iPs may be of importance in syndromes in which cyclooxygenase activation and oxidant stress coincide, such as in atherosclerosis and reperfusion after tissue ischemia.
异前列腺素（iPs）是花生四烯酸的自由基催化产物，反映体内脂质过氧化情况。几种异前列腺素在体外发挥生物学作用，可能导致氧化应激的功能后果。例如，iPF(2α)-III（8-异前列腺素F(2α)）和iPE(2)-III调节血小板功能和血管张力。尽管这些作用可被环氧化酶产物血栓素A(2)的受体（TP）拮抗剂阻断，但据推测，异前列腺素可能激活一种与TP相关但不同的受体。
构建了转基因小鼠（TPOEs），其中TP-β亚型受前内皮素原启动子控制。它们在脉管系统中过度表达TP-β，但在血小板中不表达，与野生型小鼠相比，对输注的iPF(2α)-III表现出夸张的升压反应。这可被TP拮抗作用阻断。与野生型小鼠相比，TPOEs中血小板对异前列腺素的反应未改变。相比之下，在缺乏TP基因的小鼠中，对iPF(2α)-III的升压反应及其对血小板功能的影响均被消除。输注iPE(2)-III对平均动脉压和血小板聚集的影响也是如此。
iPF(2α)-III和iPE(2)-III在体内对血小板功能和血管张力的作用，是通过作为膜TP的偶然配体而非通过独特的异前列腺素受体来实现的。异前列腺素激活TP在环氧化酶激活与氧化应激同时出现的综合征中可能具有重要意义，如动脉粥样硬化和组织缺血后的再灌注。
