Abstract
Endothelial cyclooxygenase-1-derived prostanoids, including prostacyclin, have clear cardioprotective roles associated with their anti-thrombotic potential but have also been suggested to have paradoxical pathological activities within arteries. To date it has not been possible to test the importance of this because no models have been available that separate vascular cyclooxygenase-1 products from those generated elsewhere. Here, we have used unique endothelial-specific cyclooxygenase-1 knockout mice to show that endothelial cyclooxygenase-1 produces both protective and pathological products. Functionally, however, the overall effect of these was to drive pathological responses in the context of both vasoconstriction in vitro and the development of atherosclerosis and vascular inflammation in vivo. These data provide the first demonstration of a pathological role for the vascular cyclooxygenase-1 pathway, highlighting its potential as a therapeutic target. They also emphasize that, across biology, the role of prostanoids is not always predictable due to unique balances of context, products, and receptors.
Highlights
Cyclooxygenase enzymes form part of a metabolic cascade that converts arachidonic acid into a range of prostanoid lipid mediators depending on cell-specific expression of downstream synthases
Vasoconstrictor prostanoids (PGE2, PGF2, and thromboxane) were released, and while this was at a lower level than prostacyclin (5 to 10%), it should be remembered that prostaglandin E2 (PGE2) and PGF2 have greater stability than prostacyclin and, an extended duration of action [38]. 12-hydroxyeicosatetraenoic acid (HETE) was the most abundant nonprostanoid mediator, with lower levels of other HETEs and hydroxyoctadecadienoic acids (HODEs)
Levels of 12-HETE, a product of lipoxygenase activity and the linoleic acid metabolites 9- and 13-HODEs, were unaffected by cyclooxygenase deletion. These data were validated using a pharmacological approach; we found that production of prostacyclin and the vasoconstrictor prostanoid PGE2 was reduced from A23187-stimulated aortic rings treated with the selective cyclooxygenase-1 inhibitor SC-560, but not the selective cyclooxygenase-2 inhibitor celecoxib (Table 1)
Summary
Cyclooxygenase enzymes form part of a metabolic cascade that converts arachidonic acid into a range of prostanoid lipid mediators depending on cell-specific expression of downstream synthases. The anti-thrombotic importance of cyclooxygenase-1–derived prostacyclin can be seen in endothelial cell–specific knockout mice, where loss of prostacyclin production is associated with an increase in thrombosis similar to that produced by blockade of the IP receptor [5]. Cyclooxygenase-2 protects against thrombosis; its inhibition with nonsteroidal anti-inflammatory drugs is associated with increased risk of cardiovascular events. This anti-thrombotic action is associated with cyclooxygenase-2 expression in discrete tissue locations [3] and/or vascular beds [5, 6], but is independent of systemic vascular prostacyclin production [2, 5]. The anti-thrombotic activities of vascular prostacyclin are in direct opposition to those of pro-thrombotic
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