Estrogen and the enzyme COX-2 have more in common than their ability to spark enthusiasm tainted by controversy. It turns out that one recruits the other in the blood vessels of mice. The work hints that COX-2 inhibitors may be more hazardous to women than men and may help explain how estrogen production in premenopausal females benefits the heart.
COX-2 and estrogen both impact the cardiovascular system, although scientists are still sorting out their precise effects. Estrogen has been thought to explain why premenopausal women, churning out lots of the hormone, are less likely to have heart disease than men. But 2 years ago, the Women's Health Initiative reported that older women taking hormone supplements had more, not fewer, heart problems than women on placebo. As for COX-2, in late September, drug giant Merck pulled its COX-2 inhibitor Vioxx off the market after a study found that patients on 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 Vioxx's woes (Science, 15 October, p. 384). FitzGerald's group created mice genetically susceptible to atherosclerosis and lacking the prostacyclin receptor. In these animals, there was no gender gap in heart disease, and female mice were highly susceptible to oxidative damage from free radicals, which boost plaque formation in arteries. Then the team sought to bring estrogen into the picture, turning to mice whose ovaries had been removed and who were given supplemental estrogen. The supplements increased prostacyclin biosynthesis and depressed oxidative stress, the team reports online today in Science. This suggests that in premenopausal females, estrogen stimulates COX-2 production. That boosts prostacyclin and protects against atherosclerosis, says FitzGerald. Because this estrogen-driven pathway would be much weaker in males, the work may both explain the heart disease gender gap and suggest that women who use COX-2 inhibitors may be at higher risk for atherosclerosis than men, says FitzGerald.
"[This study] opens a new option for reevaluating phenomena which we have been wondering about for decades," says Kay Brune, a pharmacologist at the University of Erlangen in Germany. Although he and others caution about extrapolating the findings to humans, Brune nonetheless calls it "potentially of enormous clinical significance."
The Science paper