Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events
Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events
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DOI：
10.1096/fj.06-6615com
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Warner, Timothy D.
中科院分区：
文献类型：
--
作者：
Mitchell, Jane A.;Lucas, Ruth;Warner, Timothy D.
最近的数据表明，经常服用非甾体抗炎药（NSAID），特别是选择性环氧合酶-2（考克斯-2）抑制剂，与血栓形成事件的风险增加有关。已经表明，这是由于NSAID由于抑制内皮考克斯-2而减少了抗血栓介质前列腺素I-2从内皮的释放。然而，在这里，我们表明，尽管正常人血管和内皮细胞含有环氧合酶-1（考克斯-1），但没有任何可检测到的考克斯-2，但血管或内皮细胞中的考克斯-1比血小板中的考克斯-1更容易被NSAID和考克斯-2选择性药物抑制（例如，例如，在一个实施例中，内皮细胞与血小板的log IC 50 +/- SEM值：萘普生-5.59 +/- 0.07 vs. -4.81 +/- 0.04;罗非昔布-4.93 +/- 0.04 vs. -3.75 +/- 0.03; n = 7）。在破碎的细胞制剂中，测试药物对内皮细胞的选择性超过血小板考克斯-1。这些观察结果表明，细胞条件的变化，如内源性过氧化物张力和底物供应，而不是环加氧酶的亚型，决定了NSAID对内皮细胞与血小板的影响。这很可能是因为血小板不是体内考克斯-1活性的良好代表，因为它在爆炸性爆发中产生前列腺素类，而不反映其他细胞的紧张性释放。本文报道的结果可以解释NSAID和考克斯-2选择性抑制剂增加心肌梗死和中风风险的明显能力。米切尔，卢卡斯河沃伊诺维奇岛Hasan，K.，佩珀，J.R.，Warner，T. D.非甾体抗炎药对内皮细胞中环氧合酶-1的抑制作用强于血小板，这为血栓形成事件风险增加提供了解释。
Recent data have suggested that regular consumption of nonsteroid anti-inflammatory drugs (NSAIDs), particularly selective inhibitors of cyclooxygenase-2 (COX-2), is associated with an increased risk of thrombotic events. It has been suggested that this is due to NSAIDs reducing the release from the endothelium of the antithrombotic mediator prostaglandin I-2 as a result of inhibition of endothelial COX-2. Here, however, we show that despite normal human vessels and endothelial cells containing cyclooxygenase-1 (COX-1) without any detectable COX-2, COX-1 in vessels or endothelial cells is more readily inhibited by NSAIDs and COX-2-selective drugs than COX-1 in platelets (e. g., log IC50 +/- SEM values for endothelial cells vs. platelets: naproxen -5.59 +/- 0.07 vs. -4.81 +/- 0.04; rofecoxib -4.93 +/- 0.04 vs. -3.75 +/- 0.03; n = 7). In broken cell preparations, the selectivities of the tested drugs toward endothelial cell over platelet COX-1 were lost. These observations suggest that variations in cellular conditions, such as endogenous peroxide tone and substrate supply, and not the isoform of cyclo-oxygenase present, dictate the effects of NSAIDs on endothelial cells vs. platelets. This may well be because the platelet is not a good representative of COX-1 activity within the body as it produces prostanoids in an explosive burst that does not reflect tonic release from other cells. The results reported here can offer an explanation for the apparent ability of NSAIDs and COX-2-selective inhibitors to increase the risk of myocardial infarction and stroke.-Mitchell, J. A., Lucas, R., Vojnovic, I., Hasan, K., Pepper, J. R., Warner, T. D. Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events.