A new approach to preventing hardening of the arteries looks promising.

California researchers report that they reduced cholesterol levels in mice by honing in on a key group of proteins. Their study appears in the Dec. 1 issue of The Journal of Clinical Investigation.

Cholesterol-lowering drugs such as statins work by lowering cholesterol in the body as a whole, explained study author Dr. Andrew C. Li, an assistant research scientist at the University of California, San Diego, Department of Cellular and Molecular Medicine in La Jolla. “But some patients still have heart attacks.”

So he and others have begun to focus on how to clear out the cholesterol from cells called macrophages - scavenger cells that eat foreign substances, including cholesterol.

“Macrophages are key players in the development of atherosclerosis,” Li said. “If you have too much cholesterol, the macrophages gobble up the bad cholesterol and try to get rid of it.” But sometimes that effort fails, and the lipid-laden cells become inflamed and form lesions on vessel walls.

In their research, Li and his team turned to a family of proteins known as peroxisome proliferator-activated receptors (PPARs). These proteins are produced by cells in vessel walls.

“PPARs have been known to play a role in helping diabetes or lowering triglycerides,” he said. “Now doctors think they may have a more direct effect in lowering atherosclerosis by altering the cholesterol metabolism in the macrophages.”

Drugs already available for diabetes or lowering triglyceride levels can activate these proteins, which can then turn on and off the genes that play a role in cholesterol metabolism, Li said.

“So we looked at three PPARs - alpha, beta, and gamma - and used three drugs that activate each one, and found that two can reduce atherosclerosis and one did not,” Li said.

“With the alpha, there was about a 50 percent reduction in lesion formation,” Li said. “With gamma, there was a 40 to 70 percent reduction in lesion formation compared to control mice. Beta had no effect.”

The new study builds on previous work and looks promising, said Dr. Peter Tontonoz, an investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles, who co-wrote an accompanying editorial.

Previous research has shown that PPAR gamma had a good effect on atherosclerosis, he said. Whether the other two help was an open question, he added.

On a practical basis, Li and Tontonoz agreed, people with cholesterol problems may be helped even more by a combination of the available cholesterol-lowering drugs and the newer agents that attack the problem on the cellular level.