NO-aspirin, No Atherosclerosis
Authors: Davenport R. John 
Published: August 2003

Modern twists on old favorites sometimes make them better. According to a new study, a redesigned aspirin molecule that delivers nitric oxide battles atherosclerosis, at least in rodents. The modified molecule keeps fatty plaques from accumulating in blood vessels and choking circulation. The study suggests that the compound, already being tested as a gut-sparing painkiller, might double as an effective plaque-buster.

The signaling molecule NO relaxes blood vessels and soothes inflammation. Previous work suggested that NO also protects blood vessels from fatty buildup: Atherosclerosis-prone mice accumulate more plaques when treated with compounds that block NO production. But whether adding NO could prevent atherosclerosis was unclear.

To further explore NO's plaque-preventing prowess, Napoli and colleagues used an old standby with a new twist: an aspirin molecule with NO attached. Researchers at NicOx, a biotech company in Sophia Antipolis, France, had designed the compound in hopes of finding a painkiller that doesn't irritate the stomach, as regular aspirin does. Napoli and colleagues wondered whether the NO-aspirin combo might also squelch fat buildup in blood vessels. The team tested NO-aspirin in mutant mice that develop extensive atherosclerosis when fed a high-cholesterol diet. These mice received regular aspirin, NO-aspirin, or a placebo for 12 weeks; the researchers then killed the animals and analyzed their blood and aortas.

Fatty deposits covered 40% less of the aorta's lining in mice given NO-aspirin than in either aspirin-dosed animals or the placebo group. In NO-aspirin treated animals, blood vessels also contained fewer macrophages: immune cells that infiltrate blood vessels and gobble cholesterol, launching atherosclerosis (see
"Purging Plaques"
). Furthermore, low-density lipoproteins suffered less oxidative damage in NO-aspirin-treated animals than in controls; such marring of these cholesterol-carrying proteins appears to exacerbate atherosclerosis by weakening plaques, increasing the likelihood that they will shatter and block blood vessels.

The results suggest that providing the animals with supplementary NO alleviates atherosclerotic damage. "I am very impressed with the magnitude of improvement they saw," says pharmacologist John Wallace of the University of Calgary in Alberta, Canada, a member of NicOx's scientific advisory board. Because the aspirin derivative releases NO slowly, he adds, it might approximate physiological amounts of NO more closely than do other compounds. Molecules that generate high concentrations of NO, such as nitroglycerin, can cause headaches and dangerously low blood pressure.

Pharmacologist Colin Funk of the University of Pennsylvania in Philadelphia is more circumspect. "If it really reduces plaque accumulation by 40%, that would be significant," he says. But recent studies have hinted that aspirin alone curtails plaque formation, says Funk, an effect that the new study doesn't replicate. Study co-author and molecular pharmacologist William Sessa of Yale University stands by the data, however, saying that little evidence supports the idea that aspirin by itself foils plaques. Trials to assess NO-aspirin's safety in humans are already under way. Perhaps the new take on the old painkiller will provide a high-performance tool for cleaning our arteries.

--R. John Davenport

C. Napoli, E. Ackah, F. de Nigris, P. Del Soldato, F. P. D'Armiento, E. Crimi, M. Condorelli, W. C. Sessa, Chronic treatment with nitric oxide-releasing aspirin reduces plasma low-density lipoprotein oxidation and oxidative stress, arterial oxidation-specific epitopes, and atherogenesis in hypercholesterolemic mice.
Proc. Natl. Acad. Sci. U.S.A.,
3 September 2002 [e-pub ahead of print].
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