November 18, 2004
Estrogen-Associated COX-2 Pathways
Protection From Heart Disease in Female Mice
Implications for Chronic Use of COX-2 Inhibitors
in Pre-Menopausal Women
(Philadelphia, PA) - Heart disease is less pronounced
in women than in men as humans age, but this difference
narrows after menopause. Some studies have shown that
estrogen slows heart disease in mouse models, but the
mechanism is largely unknown. Now scientists from the
University of Pennsylvania School of Medicine
show for the first time that in female mice protection
from hardening of the arteries purported to come from
higher levels of estrogen acts predominately through
Garret FitzGerald, MD, Chairman of
the Department of Pharmacology, and colleagues found
that estrogen binds to a cell receptor that activates
COX-2, which in turn ramps up the production of the
prostacyclin PGI2. This biochemical provides protective
benefits both by inhibiting platelet activation and
by reducing oxidative stress in the circulatory system
by increasing expression of an antioxidant enzyme. Earlier
experiments in mice by the FitzGerald lab and others
have shown that platelet activation and oxidative stress
can independently hasten hardening of the arteries.
The most recent findings appear in the November 18 issue
This study shows for the first time that prostacyclin
can modulate gender differences in atherosclerosis and
that estrogen increases prostacyclin in an animal model.
In addition, this research also demonstrates that estrogen
upregulates COX-2-dependent prostacyclin and that prostacyclin
contributes to the atheroprotective effect of estrogen.
Disabling the prostacyclin receptor in female mice
whose ovaries have been removed took away the atheroprotective
effect of estrogen. By taking away the ovaries, the
investigators can pinpoint the direct effects of estrogen.
In mice treated this way, estrogen, as expected, slows
hardening of the arteries. Eliminating the receptor
for PGI2 in those animals largely undermines this protection,
which was based on measuring the extent of atherosclerosis.
Increased platelet activation was demonstrated by increased
levels of the chemical thromboxane, and increased oxidative
stress was measured by increases of isoprostanes in
Because of the direct links among estrogen, COX-2 pathways,
and atheroprotection in female mice, this study raises
concern about the use of COX-2 inhibitors in premenopausal
women. These studies also raise the possibility of an
interaction between hormone replacement therapy and
drugs that inhibit COX-2, including traditional NSAIDs.
Of particular concern for selective inhibitors of COX-2
would be for patients with juvenile arthritis, which
involves mostly long-term drug use in young, premenopausal
women, says FitzGerald, also Director of the Institute
for Translational Medicine and Therapeutics.
Although researchers extrapolate results from mice
to humans with extreme caution, recent studies linking
COX-2 inhibitors with cardiovascular risk have focused
attention on the possibility of slowly evolving cardiovascular
risk during chronic treatment with selective COX-2 inhibitors.
This study provides insight into how this risk might
occur and identifies potential biomarkers of this evolving
The work was funded by the National Heart, Lung, and
Blood Institute of the National Institutes of Health.
Other Penn researchers on this paper were Karine M.
Egan, John A. Lawson, Susanne Fries, Daniel J. Rader,
and Emer M. Smyth, along with Beverley Koller, University
of North Carolina.
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