Fw: UT Southwestern News Release April 10, 2003

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RESEARCHERS FIND PROTEIN MECHANISM

FOR POTENTIAL ATHEROSCLEROSIS DEVELOPMENT

DALLAS – April 11, 2003 – Inactivating a protein that helps regulate the

proliferation of vascular cells increases the chance of developing

atherosclerosis, a major cause of heart disease, researchers at UT

Southwestern Medical Center at Dallas have discovered.

Vascular vessels endure constant pounding and considerable stresses

associated with blood flow. Vascular smooth muscle cells play an important

role in the development of blood vessels, providing structural integrity and

the ability to dilate and constrict. The low-density lipoprotein

receptor-related protein (LRP1) helps regulate the proliferation and

movement of these smooth muscle cells, presumably because LRP1 forms a

complex with the receptor for platelet-derived growth factor (PDGF).

In findings reported in today's issue of Science, a UT Southwestern research

team led by Dr. Joachim Herz, professor of molecular genetics and in the

Center for Basic Neuroscience, discovered that inactivating LRP1 in vascular

smooth muscle cells caused the overexpression of PDGF receptor and abnormal

PDGF receptor signaling in mice. Smooth muscle cells proliferated and the

vessel wall became highly susceptible to cholesterol buildup.

" We used gene targeting to unravel a mechanism that controls and holds

smooth muscle cell proliferation and migration in check, " said Dr. Philippe

Boucher, postdoctoral researcher in molecular genetics and first author of

the study. " This process is hyperactive in atherosclerosis. "

The absence of LRP1 is unlikely to occur in humans, Herz said, but the

research emphasizes the importance of PDGF signaling in the development of

atherosclerosis.

Atherosclerosis is a buildup of cholesterol and fatty substances in the

lining of arteries. Smooth muscle cells respond to this buildup by

proliferating and taking up more cholesterol, resulting in plaque formation.

Continued expansion of this plaque leads to arterial obstruction, which

often results in heart attack or stroke.

" We wanted to find out whether the smooth muscle cells would abnormally

proliferate after LRP1 was inactivated. They do, and the vessel wall is very

susceptible to high cholesterol, " said Herz.

The researchers also discovered that Gleevec – a drug used successfully to

treat chronic myeloid leukemia – significantly reduced the development of

the vessel abnormalities that lead to atherosclerosis. In cancer cells,

Gleevec blocks certain signals and prevents a series of chemical reactions

that cause cells to rapidly grow and divide.

" We effectively found that Gleevec could reduce atherosclerosis in our mouse

models by about 50 percent, " Herz said.

Herz cautioned that the use of Gleevec in this research does not imply it is

an alternative therapy for people with high cholesterol.

" It's better to keep cholesterol levels down and prevent these pathways from

being activated, " he said. " The key to preventing atherosclerosis has not

changed. People need to keep their blood pressure down, control cholesterol

and control diabetes. "

Other UT Southwestern researchers involved in the study were Dr. Wei-Ping

Li, assistant professor of cell biology; Dr. , chairman of

cell biology; and Dr. Gotthardt, former postdoctoral researcher at

UT Southwestern and now an assistant professor at the Max-Delbr*ck Center in

Berlin.

The research was supported by the National Institutes of Health, the

Alzheimer's Association and the Perot Family Foundation.

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This news release is available on our World Wide Web home page at

http://www.utsouthwestern.edu/home_pages/news/

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