Induction of cyclooxygenase-2 by anandamide in cerebral microvascular endothelium.
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 [(3)H]prostaglandins were produced when these cells were incubated with [3H]AEA. Incubation with R(+)-methanandamide (MAEA), a stable analogue of AEA that is not a substrate for FAAH, produced a similar increase in PGE2 production as AEA. The PGE2 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-1-mediated mechanism in cerebral microvascular endothelium.
Chen
Ping
P
Department of Biochemistry, 4-403 BSB, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Hu
Shanming
S
Yao
Jianrong
J
Moore
Steven A
SA
Spector
Arthur A
AA
Fang
Xiang
X
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology; D013687:Telencephalon / Q000098:blood supply*; D013936:Thymidine / Q000378:metabolism
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; C103505:AM 251; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C078814:anandamide; D013936:Thymidine