Aspirin and other non-specific COX inhibitors may slow atherosclerosis

March 06, 2001

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 Science.

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.
-end-



University of Pennsylvania School of Medicine

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