Why COX-2 Inhibitors Hurt the Heart

New research on the COX-2 pathway indicates that it might be possible for COX-2 drugs to achieve anti-inflammatory protection, without the cardiovascular risk, by developing drugs that target another enzyme.

Published in the May issue of the Journal of Clinical Investigation, a new study used genetically altered mice to analyze the physiological reasons for the dangerous cardiovascular side effects associated with COX-2 drugs.

The results show that COX-2 inhibitors promote heart disease by suppressing production of a fat called prostacyclin, explained lead author Garret FitzGerald.

When the receptor for prostacyclin was genetically removed from mice, the cardiovascular effects were the same as those caused by COX-2 drugs.

Prostacyclin is one of several molecules produced by COX-2 that cause pain and inflammation, FitzGerald elaborated.

But it also protects the heart by preventing blood clots, resisting artery hardening, and helping maintain balanced blood pressure.

FitzGerald's research investigated another target for anti-inflammatory drugs. Prostaglandin E2, also produced in the COX-2 pathway, has mixed effects, he said.

Prostaglandin E2 is made by an enzyme called microsomal PGE synthase-1. When microsomal PGE synthase-1 is suppressed the precursor to prostaglandin E2 is converted into prostacyclin instead.

This could mean that drugs targeting microsomal PGE synthase-1 would increase levels of prostacyclin, the opposite effect of COX-2 drugs, FitzGerald indicated. But it would probably decrease levels of prostaglandin E2.

Previous research has shown that eliminating the ability to produce microsomal PGE synthase-1 is still effective at fighting inflammation, he added.

FitzGerald believes more research is needed to understand whether drugs targeting microsomal PGE synthase-1would be effective in people.

Another product of COX-2, thromboxane, has negative effects on the heart, according to FitzGerald. But COX-2 drugs do not alter thromboxane levels.

The National Institutes of Health and Merck funded this research. Merck manufactured Vioxx (rofecoxib), a COX-2 that was pulled from the market for its cardiovascular side effects.