Cholesterol burden. When incubated with LDL cholesterol plus a cholesterol ozonolysis product, these macrophages became clogged with the lipid (red stain), which contributes to plaque formation.

Ozone May Help Clog Arteries

Cholesterol has earned a bad rap for its role in forming the artery-clogging plaques that characterize atherosclerosis and lead to heart attacks and strokes. But cholesterol has accomplices. In particular, researchers think that inflammation of blood vessels is a major instigator of plaque formation. Work described in the 7 November issue of Science now points to an intriguing new way in which inflammation may lead to cholesterol deposition in plaques.

Researchers have known for years that cholesterol oxidation is involved in plague formation, but they haven't known exactly how it gets oxidized. Not only do the new findings provide a possible explanation, they may also lead to better ways of identifying people at high risk of heart attack as well as new strategies for preventing atherosclerosis.

The current work grew out of a discovery made last year by Paul Wentworth Jr., Richard Lerner, and their colleagues at the Scripps Research Institute in La Jolla, California. They found that antibodies generate ozone from water if provided with a highly reactive form of oxygen called singlet oxygen (ScienceNOW, 15 November 2002). Ozone kills bacteria, and the finding suggested that antibodies might work in part by using ozone. In addition, the team showed that neutrophils, a type of immune cell found at inflamed sites, could provide singlet oxygen. Because antibodies are also present at inflamed sites, this raised the specter that antibody-generated ozone might contribute to the damage caused by inflammatory diseases, including atherosclerosis.

To test this idea, Wentworth and his colleagues obtained 15 surgical samples of atherosclerotic tissue. The samples produced ozone when exposed to a neutrophil-stimulating chemical, demonstrating that plaques have the equipment for ozone production. An indication that this might lead to plaque formation came from finding that the samples contain compounds produced when ozone oxidizes cholesterol. Other experiments showed that these "ozonolysis" products promote one of the steps in plaque formation: cholesterol uptake by cells called macrophages. In addition, Lerner says, they were as “toxic as hell” to blood vessel cells and thus might promote inflammation.

It's too early to say whether ozone production in plaques is a major contributor to atherosclerosis, cautions Daniel Steinberg of the University of California, San Diego. But finding out is important. “Once we know for sure [how cholesterol is oxidized],” he says, “we'll know which antioxidants will work” in suppressing plaque formation. The enzymes that generate singlet oxygen in immune cells would be one target for antiatherosclerotic drugs. The new results might also point to a better diagnostic test for ongoing inflammation in the arteries, says Samuel Wright, an atherosclerosis researcher at Merck Research Laboratories in Rahway, New Jersey.

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