Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system

Nicholas S. Kirkby, Martina H. Lundberg, Louise Harrington, Philip D.M. Leadbeater, Ginger Milne, Claire M.F. Potter, Malak Al’Yamani, Oladipupo Adeyemi, Timothy D. Warner, Jane Mitchell

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)17597-17602
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume109
Issue number43
DOIs
Publication statusPublished - 23 Oct 2012

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Cyclooxygenase 1
Epoprostenol
Cyclooxygenase 2
Cardiovascular System
Endothelium
Protein Isoforms
Cyclooxygenase 2 Inhibitors
Drug Discovery
Prostaglandin-Endoperoxide Synthases
Hormones
Enzymes

Cite this

Kirkby, Nicholas S. ; Lundberg, Martina H. ; Harrington, Louise ; Leadbeater, Philip D.M. ; Milne, Ginger ; Potter, Claire M.F. ; Al’Yamani, Malak ; Adeyemi, Oladipupo ; Warner, Timothy D. ; Mitchell, Jane. / Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system. In: Proceedings of the National Academy of Sciences. 2012 ; Vol. 109, No. 43. pp. 17597-17602.
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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.",
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Kirkby, NS, Lundberg, MH, Harrington, L, Leadbeater, PDM, Milne, G, Potter, CMF, Al’Yamani, M, Adeyemi, O, Warner, TD & Mitchell, J 2012, 'Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system', Proceedings of the National Academy of Sciences, vol. 109, no. 43, pp. 17597-17602. https://doi.org/10.1073/pnas.1209192109

Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system. / Kirkby, Nicholas S.; Lundberg, Martina H.; Harrington, Louise; Leadbeater, Philip D.M.; Milne, Ginger; Potter, Claire M.F.; Al’Yamani, Malak; Adeyemi, Oladipupo; Warner, Timothy D.; Mitchell, Jane.

In: Proceedings of the National Academy of Sciences, Vol. 109, No. 43, 23.10.2012, p. 17597-17602.

Research output: Contribution to journalArticle

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