November 10, 2003
Volume 81, Number 45
CENEAR 81 45 p. 12
ISSN 0009-2347


BIOCHEMISTRY

OZONE HAS ROLE IN ARTERIAL DISEASE
O3’s presence in narrowed arteries is evidenced by signature cholesterols

LOUISA DALTON

Ozone lives and dies within the humped plaques of a diseased artery. And as evidence of its passing, it leaves behind a pair of unique ozonated cholesterols, according to new research from Scripps Research Institute President Richard Lerner, chemist Paul Wentworth Jr., and coworkers [Science, 302, 1053 (2003)].

LIPID LOADING Ozonated cholesterols, in combination with LDLs, induce macrophages (a type of white blood cell) to pack themselves with lipids (red).
© 2003 SCIENCE
“It is most unexpected—astonishing—that this exotic trioxygen is being formed in the body,” says Daniel Steinberg, a professor of medicine at the University of California, San Diego. Ozone may be involved in the oxidation suspected to play a major role in plaque formation, he says.

This isn’t the first report of ozone’s presence in the human body. Last year, the Scripps group offered evidence that the immune system seems to be generating ozone as part of the body’s response to inflammation. “And cardiovascular disease is now quite well accepted as being a chronic low-grade inflammatory disorder,” Wentworth says. So the scientists went looking for trace evidence of ozone’s stay in atherosclerotic arteries.

They didn’t have to look far. Arterial plaques are packed with cholesterol. And ozone is the only oxidant known to cleave cholesterol’s double bond.

The group detected ozonated cholesterol in pieces of plaque so large they had to be surgically removed. Not only did the researchers find the ketoaldehyde cleavage product, but they detected its aldol condensation product as well. They also were able to activate the excised plaque’s white cells to produce more ozone.

Curious about the effects of steroids that “have never before been observed in biological systems,” Wentworth says, the Scripps collaboration further investigated whether the ozonated cholesterols contribute to artery hardening. Indeed, the compounds damage arterial cells and, along with low-density lipoproteins (LDLs), induce white cells to gather up lipids in one of the first steps of arterial disease.

“What this does is add another way in which oxidative processes may be important in atherosclerosis,” Steinberg says. He and others have spent years amassing evidence that the oxidation of LDLs and cholesterol is a key component of artery hardening. They’ve proposed three or four other mechanisms for how cholesterol, LDLs, and the lipids inside LDLs become oxidized. Here, he says, is yet another option. “However, the amounts [of oxidized products] are really tiny,” Steinberg says. Determining “whether those are going to be enough to play a role in the overall atherosclerotic process obviously remains for future experiments.”

The unique compounds detected by the Scripps group may be useful in one other way, according to Wentworth. The aldol condensation product is stable enough to enter the bloodstream, and the Scripps group is setting up a clinical trial to use the molecule as a diagnostic marker for heart disease. In a small preliminary trial, Wentworth says, they found the steroid in the blood of six out of eight patients eligible for surgical plaque removal and in only one out of 15 patients with no signs of heart disease.

Perhaps, he says, this product of ozone’s passing can be an early warning for the often-undetected buildup of plaque in the arteries.

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