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Researchers find enzyme that triggers hardening of the arteries

WINSTON-SALEM, N.C. An enzyme found only in the liver and intestines may play a crucial role in the development of hardening of the arteries -- or atherosclerosis, a research team from Wake Forest University Baptist Medical Center and the University of California, San Francisco, report in the Proceedings of the National Academy of Sciences.

The narrowing of arteries through atherosclerosis is a major contributor to heart attacks and strokes.

The confirmation of the relationship between the enzyme, ACAT2, and low density lipoproteins (LDL -- the bad cholesterol) may point to a new way of treating hardening of the arteries.

"Our results support the rationale of pharmacological inhibition of ACAT2 as a possible therapy for atherosclerosis," said Lawrence L. Rudel, Ph.D., professor of comparative medicine and biochemistry at Wake Forest.

Rudel and his colleagues said the study demonstrates that ACAT2 was "crucial for the development of atherosclerosis in mice." The work was all done in mice from an atherosclerosis susceptible strain, because mice are the only animals that can be genetically modified to test the disease process. Knockout mice were developed that were missing the gene that makes ACAT2, and therefore had almost none of the enzyme. These mice were compared to controls that had normal levels of ACAT2.

"The absence of ACAT2 in the small intestine and liver almost completely prevented the development of atherosclerosis," they said. "These studies implicate ACAT2 activity as a major determinant of susceptibility to atherosclerosis."

They found that total cholesterol levels were nearly 2 1/2 times lower in the knockout mice than in the control mice.

Ordinarily, said Rudel, some cholesterol is modified so that it can be transported from the liver to the body's tissues. The ACAT2 enzyme performs the modification by attaching a fatty acid to the cholesterol molecule, creating a cholesterol ester ca
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Contact: Robert Conn, Karen Richardson or Barbara Hahn
rconn@wfubmc.edu
336-716-4587
Wake Forest University Baptist Medical Center
20-Jan-2003


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