A COX-2 inhibitor (right) increases the expression of tissue factor (red) in heart vessels (arrows).

On page 2053, Ghosh et al. reveal how antiinflammatory COX-2 inhibitors cause dangerous cardiac side effects. COX-2, they find, is needed to shut off an important clotting protein.

COX-2 is produced during infection and injury by the endothelial cells that line blood vessels. The enzyme converts a cellular lipid known as arachidonic acid into lipids that instigate fever, pain, and other uncomfortable hallmarks of inflammation.

COX-2 inhibitors such as Vioxx were popular antiinflammatory drugs until some users began to suffer serious side effects such as heart attack and stroke.

Ghosh et al. now find that the normally cardioprotective effect of COX-2 stems from its metabolic conversion not of arachidonic acid, but of other substrates: the endocannabinoids. Byproducts of these lipids, they found, activated a nuclear receptor and transcription factor, PPARδ, that suppressed the gene for tissue factor (TF)—a protein that activates blood clotting. Mice that were given COX-2 inhibitors had high levels of TF that could then be decreased by activating PPARδ. The side effects triggered by the COX-2 inhibitors in humans may thus be due to the overproduction of TF.

COX-2's anticlotting role probably keeps injured vessels free of clots while the damage is being repaired. The team is now investigating whether patients who have adverse reactions to the drugs have defects in TF or other clotting genes.