How Prostaglandins Affect the Cardiovascular System

Researchers have unraveled the balanced relationship between prostacyclin (PGI2) and thromboxane (TxA2), two prostaglandin products of the cyclo-oxygenase enzymes (COX-1 and COX-2), and their potential relevance to cardiovascular disease. Their findings appear in the April 19, 2002, issue of Science.

COX-1, the form of cyclo-oxygenase found in platelets, makes TxA2, which causes blood vessels to constrict and platelets to become sticky, a primary step in heart attack or stroke. COX-2, by contrast, is expressed in blood vessels and is a major source of PGI2, which dilates blood vessels and prevents the activation of platelets. Thus, drugs that block COX-1 can thin the blood, while drugs that block COX-2 can decrease pain associated with inflammation.

"Aspirin has been proven effective in lowering the risk of a second heart attack or stroke by blocking TxA2 formation by COX-1, thereby thinning the blood,” said Dr. Garret A. FitzGerald, of the University of Pennsylvania School of Medicine (Philadelphia, USA; www.med.upenn.edu). "We had previously found evidence that selective COX-2 inhibitors, which are prescribed for the relief of pain and inflammation, can allow TxA2 formation to go unchecked by suppressing the production of PGI2. We wished to investigate the likely importance of this observation by clarifying the interplay of the two COX products in the cardiovascular system.”

In the current study, the researchers showed that injury-induced vascular proliferation and platelet activation were enhanced in mice that were genetically deficient in the PGI2 receptor but were depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2.

This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2. "We were struck by the increase in thromboxane formation when prostacyclin was unable to work and wondered if it mediated the consequences of removing the PGI2 receptor,” said Dr. Yan Cheng, first author on the paper. The evidence that PGI2 restrains the harmful cardiovascular effects of TxA2 in vivo will be an important consideration in the development of new cardiovascular drugs.



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