Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: Selective up-regulation of prostacyclin synthesis by COX-2
Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: Selective up-regulation of prostacyclin synthesis by COX-2
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DOI：
10.4049/jimmunol.167.5.2831
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发表时间：
2001-09-01
影响因子：
4.4
通讯作者：
James, MJ
中科院分区：
文献类型：
--
作者：
Caughey, GE;Cleland, LG;James, MJ
两种环氧合酶（考克斯）亚型，考克斯-1和考克斯-2，均将花生四烯酸代谢为PGH（2），PGH（2）是血栓烷A（2）（TXA（2））、前列环素（PGE（2））和PGE（2）合成的共同底物。我们的特点是这些前列腺素类化合物的合成在HUVECs与考克斯-1和考克斯-2的活性。未处理的HUVEC仅表达考克斯-1，而加入IL-1 β可诱导考克斯-2。TXA（2）是主要的考克斯-1衍生产物，IL-1 β上调考克斯-2后，TXA（2）的合成几乎没有变化（增加2倍）。相反，考克斯-2上调与PGI（2）和PGE（2）合成的大幅增加相关（分别增加54倍和84倍）。加入选择性考克斯-2抑制剂NS-398几乎完全抑制PGI（2）和PGE（2）的合成，但对TXA（2）的合成影响不大。IL-1 β上调考克斯-2的同时特异性上调PGI合酶和PGE合酶，但不上调TX合酶。对底物浓度依赖性的研究表明，TXA（2）合成途径在花生四烯酸浓度比PGI（2）和PGE（2）合成途径低20倍时饱和。总之，内皮前列腺素类合成似乎受到考克斯-2诱导的差异调节。PGI（2）和PGE（2）与考克斯-2活性的明显联系可以通过总考克斯活性的暂时增加、PGI合酶和PGE合酶的选择性上调以及末端酶的不同动力学特征来解释。这些发现对于考克斯-2抑制的心血管后果的可能性具有特别重要的意义。
The two cyclooxygenase (COX) isoforms, COX-1 and COX-2, both metabolize arachidonic acid to PGH(2), the common substrate for thromboxane A(2) (TXA(2)), prostacyclin (PGE(2)), and PGE(2) synthesis. We characterized the synthesis of these prostanoids in HUVECs in relation to COX-1 and COX-2 activity. Untreated HUVEC expressed only COX-1, whereas addition of IL-1 beta caused induction of COX-2. TXA(2) was the predominant COX-1-derived product, and TXA(2) synthesis changed little with up-regulation of COX-2 by IL-1 beta (2-fold increase). By contrast, COX-2 up-regulation was associated with large increases in the synthesis of PGI(2) and PGE(2) (54- and 84-fold increases, respectively). Addition of the selective COX-2 inhibitor, NS-398, almost completely abolished PGI(2) and PGE(2) synthesis, but had little effect on TXA(2) synthesis. The up-regulation of COX-2 by IL-1 beta was accompanied by specific up-regulation of PGI synthase and PGE synthase, but not TX synthase. An examination of the substrate concentration dependencies showed that the pathway of TXA(2) Synthesis was saturated at a 20-fold lower arachidonic acid concentration than that for PGI(2) and PGE(2) synthesis. In conclusion, endothelial prostanoid synthesis appears to be differentially regulated by the induction of COX-2. The apparent PGI(2) and PGE(2) linkage with COX-2 activity may be explained by a temporal increase in total COX activity, together with selective up-regulation of PGI synthase and PGE synthase, and different kinetic characteristics of the terminal synthases. These findings have particular importance with regard to the potential for cardiovascular consequences of COX-2 inhibition.