Daily University Science News
Making sure
cardiac patients take an aspirin a day to prevent a second heart
attack is part of established treatment for most physicians, and
many recommend the same regimen for patients at risk of suffering
a first attack.
But there
has never been scientific evidence to demonstrate that this common,
over-the-counter medication really provides any benefit in staving
off the underlying condition of atherosclerosis.
Now, mouse-model
research by scientists at the University of Pennsylvania School
of Medicine has demonstrated that aspirin, ibuprofen and other
drugs in the class of pharmaceuticals known as non-specific COX
inhibitors may aid substantially in preventing heart disease,
slowing the build-up of plaque in blood vessels by more than 50
percent.
"This
study suggests that a product of the cyclooxegenase enzyme known
as COX-1 -- which is the form targeted by aspirin in the prevention
of heart attacks -- may also have a part to play in the gradual
hardening of the arteries that precedes acute events like heart
attack or stroke," said Garret A. FitzGerald, MD, chairman
of Penn’s Department of Pharmacology. The research will be
published March 13 in the Proceedings of the National Academy
of Sciences.
The study
also demonstrates that a separate class of drugs that specifically
target the COX-2 enzyme -- so-called “super aspirins”
such as Celebrex and Vioxx -- do not speed up the development
of atherosclerosis, a concern based on some biochemical effects
of those drugs.
In their work,
the Penn scientists scrutinized both known forms of the enzyme
cyclooxygenase: COX-1, which is present throughout the body, and
COX-2, which is present in some tissues, including the lining
of the blood vessels.
COX-1 is the
only form of the enzyme in platelets -- blood cells that stick
together in the first stages of clotting. Suppression of the platelet
COX-1 product, thromboxane, is how aspirin protects against heart
attack and stroke.
The COX-2
enzyme produces prostacyclin, a hormone-like substance that might
work against atherosclerosis by keeping blood vessels elastic,
slowing the division of cells in the blood vessel wall, and preventing
blood clots. On the other hand, prostacyclin is also pro-inflammatory
-- a property that may speed up atherosclerosis. Before the experiment,
it was impossible to know how these conflicting effects would
play out when COX-2 inhibitors were given.
When they
were introduced a few years ago as anti-inflammatories, the COX-2
inhibitors quickly became popular for treating illnesses such
as arthritis. But because of the properties of prostacyclin, FitzGerald
and his colleagues wondered whether blocking this COX-2 product
might lead to hardening of the arteries, particularly in young
patients with juvenile arthritis who might take the drug for long
periods.
Using mice
that had been engineered to produce high levels of cholesterol,
the scientists injected one group with the non-specific inhibitor
indomethacin, a second group with the COX-2 blocker nimesulide,
and a third control group with a placebo. Analyzing the mice’s
aortas at the conclusion of the 16-weeks study, the researchers
found that atherosclerotic lesions were reduced by 55 percent
in mice exposed to the non-specific COX inhibitor, compared to
lesions in the untreated mice. Mice exposed to the COX-2 inhibitor
showed the same progression of atherosclerosis as the control
group.
"Because
prostacyclin is potentially pro-inflammatory, inhibiting it might
have proved beneficial, and there was a hint of that in our data.
But it did not attain significance – in fact the effects
of inhibiting prostacyclin paled in comparison with the use of
a mixed inhibitor," FitzGerald said.
"The
real story is that atherosclerosis is not only inflammation. There
is something else at work here, and that is the production of
thromboxane by COX-1," added Domenico Pratico, MD, a research
assistant professor of Pharmacology at Penn who collaborated with
FitzGerald in the study.
The research
was funded by grants from the American Heart Association and the
National Institutes of Health. Others assisting in the study were
Cyrus Tillman, Zhi-Bing Zhang and Hongwei Li, all of Penn. - By
Ellen O'Brien
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