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Cox2 reporter gene expression and prostacylin mass spectrometry confirm vascular COX‐1 dominance for prostacyclin production
Author(s) -
Kirkby Nicholas S,
Zaiss Anne K,
Urquhart Paula,
Jiao Jing,
Austin Philip J,
Warner Timothy D,
Nicolaou Anna,
Herschman Harvey R,
Mitchell Jane A
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb507
Subject(s) - prostacyclin , gene isoform , medicine , endocrinology , context (archaeology) , chemistry , gene , biology , biochemistry , paleontology
Prostacyclin is an endothelium‐derived anti‐thrombotic hormone, whose synthesis requires cyclo‐oxygenase (COX) activity. Two COX isoforms exist. It is widely held that COX‐2 drives prostacyclin production and that this explains the cardiovascular toxicity of COX‐2 inhibitors, but this supposition relies on indirect evidence from urinary markers. We previously demonstrated that COX‐1 is the dominant isoform for vascular prostacyclin release (Kirkby et al PNAS 2012), however, this work was criticized (Ricciotti et al PNAS 2012) because it relied on immunoassay and immunohistochemistry methods. To address this, we measured prostanoid levels by mass spectrometry in mouse plasma and found levels similar to immunoassay values, which were reduced (>;80%) by Cox1 , but not by Cox2 deletion. Using a Cox2 luciferase reporter mouse we also confirmed that there is little gene expression from the aorta, other large arteries or veins. In contrast, thymus, brain and gut expressed much higher levels (Figure 1). These data are consistent with the conclusion that COX‐1 drives vascular prostacyclin release, allays previous criticisms, and puts the weak vascular COX‐2 expression in the context of other tissues. They also suggest target tissues to consider in developing much needed new ideas of how COX‐2 protects the cardiovascular system.