PA) - Cyclooxygenase (COX) is a pharmacologically important
enzyme that has a role in blood clotting and inflammation.
The relationship between its two major forms and their
products, however, has been largely undefined. In the
April 19th issue of the journal Science, researchers
at the University of Pennsylvania School of Medicine
explain the balanced relationship between two products
of the cyclooxygenases - prostacyclin (PGI2) and thromboxane
(TxA2) - and their potential relevance to cardiovascular
disease and the effects of selective inhibitors of COX-2,
such as Merck's Vioxx and Pharmacia / Upjohn's Celebrex.
COX-1, the form of cyclooxygenase found
in platelets, makes TxA2, which causes blood vessels
to constrict and platelets to become sticky - the first
step in a heart attack or stroke. COX-2, by contrast,
is expressed in blood vessels and is a major source
of prostacyclin (PGI2), which dilates blood vessels
and prevents the activation of platelets. Drugs that
block COX-1 can thin blood, while drugs that block COX-2
can decrease pain associated with inflammation.
"Aspirin has been proven effective in
lowering the risk of a second heart attack or stroke
by blocking TxA2 formation by COX - 1, thereby thinning
the blood," said Garret A. FitzGerald, MD,
chair of the Penn Department of Pharmacology and director
of the Penn Center for Experimental Therapeutics. "We
had previously found evidence that selective COX-2 inhibitors,
which are prescribed for the relief of pain and inflammation
can allow TxA2 formation to go unchecked by suppressing
the production of PGI2. We wished to investigate the
likely importance of this observation by clarifying
the interplay of the two COX products in the cardiovascular
FitzGerald observed almost twenty years
ago that formation of both thromboxane and prostacyclin
is increased in patients with heart and blood vessel
disease who benefit from aspirin. Given their opposing
actions, he speculated that PGI2 production is stimulated
as a response to platelet interactions with the vessel
wall, to limit the harmful effects of thromboxane on
the cardiovascular system - a speculation that the Science
In mice bred to lack receptors for PGI2,
FitzGerald and his colleagues showed that both the vascular
response to injury and the corresponding activation
of platelets were both markedly exaggerated. Similarly,
mice that over-expressed receptors for TxA2 also produced
these exaggerated effects. The effect was diminished
when researchers either deleted the TxA2 receptor or
blocked the receptor using an experimental drug. When
the researchers deleted both the TxA2 receptor and the
PGI2 receptor, it cancelled out the effect of inactivating
the PGI2 receptor alone.
"We were struck by the increase in thromboxane
formation when prostacyclin was unable to work and wondered
if it mediated the consequences of removing the PGI2
receptor," said Yan Cheng MD, PhD, first author on the
paper. FitzGerald's group had shown previously that
formation of both TxA2 and PGI2 are increased by percutaneous
coronary angioplasty (PCA), a procedure mimicked in
the animal studies. In humans, aspirin halves the chances
of a heart attack complicating PCA.
The evidence that PGI2 restrains the harmful
cardiovascular effects of TxA2 in vivo may have relevance
to three important classes of cardiovascular drugs.
Firstly, coincidental inhibition of both COX products
may limit the effectiveness of aspirin. Indeed, an experimental
formulation of aspirin that only targets platelets was
developed by FitzGerald in collaboration with the Bayer
corporation and has been shown to be effective in heart
attack prevention. However, whether it is superior to
conventional forms of aspirin has never been assessed.
Secondly, TxA2 receptor antagonists bypass suppression
of PGI2 and may offer advantages over aspirin. The antagonist
used in the Science study is under development by Servier.
Finally, FitzGerald and colleagues reported several
years ago that selective inhibitors of COX-2 inhibit
PGI2, but not TxA2. The possibility that such drugs
might constitute a cardiovascular risk has since attracted
"While such a clinical risk is far from
established," said FitzGerald, "our results afford a
credible mechanism by which a cardiovascular hazard
might occur in that minority of individuals predisposed
The study was supported by the National
Heart Lung and Blood Institute of the National Institutes
of Health and by a grant from the Servier Company.
# # #
Editor's Note: Dr. FitzGerald does
not have any financial stake in Bayer Pharmaceuticals,
Merck, Servier, or Pharmacia/Upjohn.
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