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*
Rheumatology Unit, Royal Adelaide Hospital, and
Division of Human Immunology, Hanson Centre for Cancer Research, Adelaide, South Australia, Australia
The two cyclooxygenase (COX) isoforms, COX-1 and COX-2, both
metabolize arachidonic acid to PGH2, the common substrate
for thromboxane A2 (TXA2), prostacyclin
(PGI2), and PGE2 synthesis. We characterized
the synthesis of these prostanoids in HUVECs in relation to COX-1 and
COX-2 activity. Untreated HUVEC expressed only COX-1, whereas addition
of IL-1
caused induction of COX-2. TXA2 was the
predominant COX-1-derived product, and TXA2 synthesis
changed little with up-regulation of COX-2 by IL-1 (2-fold
increase). By contrast, COX-2 up-regulation was associated with large
increases in the synthesis of PGI2 and PGE2
(54- and 84-fold increases, respectively). Addition of the selective
COX-2 inhibitor, NS-398, almost completely abolished PGI2
and PGE2 synthesis, but had little effect on
TXA2 synthesis. The up-regulation of COX-2 by IL-1 was
accompanied by specific up-regulation of PGI synthase and PGE synthase,
but not TX synthase. An examination of the substrate concentration
dependencies showed that the pathway of TXA2 synthesis was
saturated at a 20-fold lower arachidonic acid concentration than that
for PGI2 and PGE2 synthesis. In conclusion,
endothelial prostanoid synthesis appears to be differentially regulated
by the induction of COX-2. The apparent PGI2 and
PGE2 linkage with COX-2 activity may be explained by a
temporal increase in total COX activity, together with selective
up-regulation of PGI synthase and PGE synthase, and different kinetic
characteristics of the terminal synthases. These findings have
particular importance with regard to the potential for cardiovascular
consequences of COX-2 inhibition.
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