Unprotected. Plates (red) distributed in the arteries of female mice lacking a key receptor.
estrogen and the COX-2 enzyme have more in common than their ability to generate excitement marred by controversy. It happens that we recruit the other blood vessels in mice. The work suggests that COX-2 inhibitors may be more dangerous for women than men and may help explain how the production of estrogen in premenopausal women has the heart.
COX-2 and estrogen both impact the cardiovascular system, although scientists are still sorting out their precise effects. Estrogen is thought to explain why premenopausal women, churning much of the hormone, are less likely to have heart disease than men. But 2 years ago, Initiative on Women's Health reported that older women who take hormone supplements had more, not less, heart problems than women on placebo. As COX-2, in late September, pharmaceutical giant Merck pulled its COX-2 inhibitor Vioxx from the market after a study showed that patients taking Vioxx suffered more heart attacks.
Garret FitzGerald, a pharmacologist and cardiologist at the University of Pennsylvania and a critic of COX-2 inhibitors, was curious about a fatty acid called prostacyclin, which is produced by COX-2. Cardiologists consider the loss of prostacyclin a likely culprit behind the misfortunes of Vioxx ( Science , 15 October, p. 384). The group FitzGerald created genetically susceptible to atherosclerosis and mouse receptor without the prostacyclin. In these animals, there was no gender gap in heart disease and female mice were highly susceptible to oxidative damage from free radicals that stimulate the formation of plaque in the arteries. Next, the team sought to make estrogen in the image, turning to mice whose ovaries were removed and received estrogen supplement. The supplements increased prostacyclin biosynthesis and depressed oxidative stress, the team reports online today in Science . This suggests that in premenopausal women, estrogen stimulates COX-2 production. This stimulates prostacyclin and protects against atherosclerosis, said FitzGerald. Because this route leads would be much lower estrogen in men, the work may also explain the gender gap in heart disease and suggest that women who use COX-2 inhibitors may be at greater risk for atherosclerosis that men, says FitzGerald.
"[This study] opens a new option for reassessing phenomena we have been wondering about for decades," says Kay Brown, a pharmacologist at the University of Erlangen in Germany. Although he and other cautioned about extrapolating the results to humans, Brunette nevertheless called it "potentially enormous clinical significance."
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