title: Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system.
abstract: Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.
authors.affiliation: Cardiothoracic Pharmacology, National Heart and Lung Institute,  Imperial College, London SW3 6LY,  United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: Martina H
authors.initials: MH
authors.lastname: Lundberg
authors.forename: Louise S
authors.initials: LS
authors.lastname: Harrington
authors.forename: Philip D M
authors.initials: PD
authors.lastname: Leadbeater
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Claire M F
authors.initials: CM
authors.lastname: Potter
authors.forename: Malak
authors.initials: M
authors.lastname: Al-Yamani
authors.forename: Oladipupo
authors.initials: O
authors.lastname: Adeyemi
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002319:Cardiovascular System / Q000378:metabolism*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2