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.

COX-2, the dominant source of prostacyclin

“…Subsequently, we confirmed that PGIM was markedly suppressed by global deletion or inhibition of COX-2 in mice, consistent with results of Kirkby et al (1). However, the authors claimed PGIM is not reflective of vascular PGI 2 , reporting that infusion of a vascular stimulant, bradykinin, evokes COX-1-derived immunoreactive 6-keto PGF 1α , but not PGIM, in mice.…”

“…Kirkby et al (1) failed to mention that deletion of COX-2 in vascular, smooth muscle cells, or both depressed urinary PGIM, providing direct genetic evidence for the role of vascular COX-2 in PGI 2 production (5). They also ignored the functional consequences of vascular deletion of COX-2, a predisposition to thrombosis and hypertension, or that urinary PGIM (alone among the major metabolites of PGs was suppressed in these mutants) inversely correlated with the rise in blood pressure (5), consistent with the hypothesis that the hypertensive phenotype is a consequence of disruption of COX-2-dependent formation of PGI 2 .…”

“…In a recent issue of PNAS, Kirkby et al (1) claimed that cyclooxygenase (COX)-1, not COX-2, is the dominant source of prostacyclin (PGI 2 ). This conclusion was based on experiments using a flawed approach to estimating enzyme activity and PGI 2 formation and a selective omission of data in the literature.…”

“…Kirkby et al (1) used an immunoassay of 6-keto prostaglandin (PG)F 1α to reflect PGI 2 . However, their reported levels (∼150 ng/mL) were orders of magnitude higher than when 6-keto PGF 1α is measured (<3 pg/mL) in plasma by mass spectrometry (MS) (2).…”

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

“…There are two COX isoforms: COX-1 and COX-2. COX-1 is a constitutive, housekeeping enzyme that is ubiquitously expressed and is responsible for prostanoid production in most tissues (1). In contrast, COX-2 is an inducible enzyme, expressed at sites of inflammation, infection, and cancer (2) that generates prostanoids that drive disease pathogenesis.…”