Protein Inhibits Atherosclerosis

Discovery could lead to treatments for this potential killer

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HealthDay Reporter

THURSDAY, April 10, 2003 (HealthDayNews) -- Researchers have discovered a protein that helps stave off atherosclerosis in mice.

What's more, the human cancer drug Gleevec seems to work as a surrogate for the protein in mice who lacked the compound.

The real value of the research may lie in what it contributes to our body of knowledge of atherosclerosis, rather than any direct treatment for the condition, commonly known as hardening of the arteries.

The study appears in the April 11 issue of Science.

"This is one of a hundred articles that are going to begin to tease away the various complex mechanisms that allow the blood vessel to repair itself if it's injured," says Dr. Richard Stein, chief of cardiology at Brooklyn Hospital Center in New York City and a spokesman for the American Heart Association.

"That's a normal biological process, but we're learning that all of these processes, if they're not properly modulated, will go on to cause atherosclerosis inside the wall of the artery," he says.

Atherosclerosis occurs when plaque -- made up of fatty compounds, cholesterol and other substances -- builds up inside an artery. Sometimes, enough plaque accumulates to disrupt blood flow. More often, pieces can break off to form dangerous blood clots that can cause heart attacks or strokes.

The body's natural response to high cholesterol levels is to dispatch a growth factor which, in turn, summons smooth muscle cells to thicken and harden the arteries so they can continue to withstand the constant pressure and stress of flowing blood. As long as the process is regulated, all's well. But too much growth factor makes the problem worse.

"Platelet-derived growth factor is a normal part of repair if the wall is injured. But overstimulation of this will cause progression" of atherosclerosis," Stein says.

As the authors of the current study discovered, a protein called LRP1 can bind with the growth factor's receptor to inhibit this process.

"This was the first evidence of a new role for that receptor. It's a completely different function," says Philippe Boucher, lead author of the study and a postdoctoral researcher at the University of Texas Southwestern Medical Center at Dallas.

"When LRP1 is not there, the pathway is not regulated. Then you have this migration and proliferation of cells that we observed. On top of that, if you give a high-fat diet, mice develop a hypersensitivity to developing atherosclerosis," he says.

Boucher and his colleagues looked at mice who had been genetically engineered not to have the LRP1 protein. Sure enough, the absence of the protein allowed the growth factor to go wild and led to an excessive buildup of smooth muscle cells.

When the drug Gleevec was given to the mice, the excessive proliferation of smooth muscle cells subsided. The drug seemed to have a protective effect even when the mice were fed a high-cholesterol diet. Gleevec was originally developed for conditions related to atherosclerosis, but has been found to be much more successful in treating different human cancers, particularly chronic myeloid leukemia.

"Gleevec basically inhibits the activation of smooth muscle cell receptors so it acts a little bit like LRP1," Stein says. "It prevented the enhancement of atherosclerosis in mice."

The research is especially important if your goal is to have healthier, longer-living mice, particularly if those mice eat badly, Stein quips. But it's not ready for human prime time.

"They've shown that it works in this strange, genetically modulated mouse, but there's no evidence that people lack that protein," Stein says.

The first hurdle is to find out if the right process has been pinpointed, Boucher says.

"Gleevec is doing a lot of things besides blocking the pathway, so to make sure this is really the pathway that is disrupted in those animals, we need to genetically block the pathway," he says.

And then even more animal studies are needed before human studies can be attempted.

"If we were going to find a magic drug or natural ingredient, probably we would have found it already. That's not the way we're going to work our way out of this problem," Stein says.

"We're going to do that by understanding the biology of vascular growth repair and atherosclerosis and knowing enough to intervene in a delicate, precise surgical manner in that process so as to inhibit atherosclerosis but not damage the normal repair processes that are built into vessels. These are important first steps."

More information

For more on atherosclerosis, visit the American Heart Association or the International Atherosclerosis Society.

SOURCES: Philippe Boucher, Ph.D., postdoctoral researcher, University of Texas Southwestern Medical Center, Dallas; Richard Stein, M.D., spokesman, American Heart Association, professor, clinical medicine, Weill Cornell Medical Center, and chief, cardiology, Brooklyn Hospital Center, both in New York City; April 11, 2003, Science

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