Induction of cyclooxygenase-2 by anandamide in cerebral microvascular endothelium
Induction of cyclooxygenase-2 by anandamide in cerebral microvascular endothelium
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DOI：
10.1016/j.mvr.2005.02.001
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Fang, X
中科院分区：
文献类型：
--
作者：
Chen, P;Hu, SM;Fang, X
阿南达胺(AEA)是一种内源性大麻素受体激动剂，是脑微循环中的一种强有力的血管扩张剂。AEA被脂肪酸氨基水解酶(FAAH)转化为花生四烯酸(AA)，AA转化为前列腺素被认为是血管扩张的潜在机制。虽然AEA刺激小鼠脑微血管内皮细胞产生前列腺素，但当这些细胞与[H-3]AEA孵育时，不产生[H-3]前列腺素。与不是FAAH底物的AEA的稳定类似物R(+)-甲酰胺(MAEA)孵育，产生与AEA相似的PGE(2)产量增加。选择性环氧合酶(COX)-2抑制剂NS-398可完全抑制AEA或MAEA诱导的PGE(2)产生，提示COX-2被诱导。AEA和MAEA以时间依赖的方式增加COX-2蛋白的表达。选择性大麻素受体-1拮抗剂AM-251可部分抑制AEA诱导的COX-2蛋白表达。此外，AEA使COX-2启动子活性在-1432至+59(COX-2启动子全长)的范围内增加约两倍，AM-251可部分抑制AEA引起的COX-2启动子活性的增加。这些结果表明，AEA在转录水平上增加了COX-2的表达，至少部分是通过大麻素受体-I介导的脑微血管内皮细胞机制。(C)2005 Elsevier Inc.保留所有权利。
Anandamide (AEA), an endogenous cannabinoid receptor agonist, is a potent vasodilator in the cerebral microcirculation. AEA is converted to arachidonic acid (AA) by fatty acid amidohydrolase (FAAH), and the conversion of AA to prostaglandins has been proposed as a potential mechanism for the vasodilation. Although AEA stimulated prostaglandin production by mouse cerebral microvascular endothelial cells, no [H-3]prostaglandins were produced when these cells were incubated with [H-3]AEA. Incubation with R(+)-methanandamide (MAEA), a stable analogue of AEA that is not a substrate for FAAH, produced a similar increase in PGE(2) production as AEA. The PGE(2) production induced by either AEA or MAEA was completely inhibited by NS-398, a selective cyclooxygenase (COX)-2 inhibitor, suggesting that COX-2 was induced. AEA and MAEA increased the expression of COX-2 protein in a time-dependent manner. This increase occurred as early as 1 h and reached maximum at 2 h. Induction of COX-2 protein by AEA was partially inhibited by AM-251, a selective cannabinoid receptor-1 antagonist. Furthermore, AEA increased COX-2 promoter activity approximately twofold above baseline in a fragment ranging from -1432 to +59, the full-length of the COX-2 promoter, and the increase in COX-2 promoter activity produced by AEA was partially inhibited by AM-251. These results indicate that AEA increased COX-2 expression at the transcriptional level through, at least in part, a cannabinoid receptor-I-mediated mechanism in cerebral microvascular endothelium. (c) 2005 Elsevier Inc. All rights reserved.