Cox-2 Linked to Heart Protection

BIOCHEMISTRY

Researchers have placed a key piece into one of the unfinished puzzles of heart research: why females, compared with males, have a decreased risk of heart disease before they go through menopause. The work is interesting in light of data showing an increased risk of heart attack or stroke in people taking the analgesic Vioxx.

Young female mice, it turns out, take their benefit from the cardioprotective fatty acid prostacyclin. Prostacyclin production, in turn, depends on the activation of the enzyme cyclooxygenase-2, or COX-2 [Science, published online Nov. 19, http://dx.doi.org/10.1126/science.1103333].

The finding offers an important but likely not exclusive way that COX-2 is involved in heart protection, says professor of pharmacology Garret A. FitzGerald at the University of Pennsylvania School of Medicine and lead author of the study.

In mouse models of heart disease, fertile females are slower to develop damaged, narrowed vessels than are males, just as in humans. When FitzGerald and coworkers knocked out the gene for the prostacyclin receptor in these mice, they found that both sexes developed the disease at the same rate. "The females caught up with the males in terms of atherosclerotic risk," FitzGerald says. The effect was especially pronounced in the early stages of the disease, at initiation of the pathways that lead to clogged arteries, such as platelet activation and oxidative stress.

FitzGerald and coworkers subsequently discovered that estrogen underlies the heart protection in female mice. Estrogen is abundant in premenopausal women. Activation of one of its receptors increases the activity of COX-2 and subsequently increases the production of prostacyclin.

What do these findings mean for humans? And what might they suggest about COX-2 inhibitor drugs such as Vioxx? Merck recently withdrew Vioxx because it raises cardiovascular risk, but the related Pfizer drugs, Celebrex and Bextra, are still on the market.

"You have to be very careful in extrapolating from models to humans," FitzGerald says. However, he adds, "estrogen's protective effect in premenopausal females might be undermined to some extent by inhibition of COX-2." Discovery of this pathway in mice, he says, raises concern about administering COX-2 inhibitors to premenopausal women--for example, young women who take COX-2 inhibitors for juvenile arthritis.

This is an elegant study that "connects the dots between estrogen receptor, prostacyclin, and plaque development in the mouse model," comments Eric Topol, department chairman of cardiovascular medicine at the Cleveland Clinic. Yet making any clinical link to humans is speculation, he adds. "This is a study of the pathway. It is not a study trying to ferret out why [COX-2 inhibitors] could induce heart attacks or strokes."

Topol points out that the data that associate Vioxx with heart attacks and stroke show no apparent difference in risk for men versus women.

Yet a gender difference likely wouldn't show up in the clinical studies on COX-2 inhibitors done so far, FitzGerald says. Only 1 to 2% of the patients who took Vioxx longer than 18 months had any trouble with heart attacks or stroke. "Because absolute numbers of events are so low, you can't establish any significant differences between the genders."

The value of the mouse study, FitzGerald says, "is that it is raising a lot of questions." It offers a way to connect COX-2 to protection of blood-vessel walls and links it to the cardiovascular protection women enjoy before menopause.