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Lack Of A Gene Cuts Blood Vessel Damage In Mice 70%

In a new study, when a strain of mice prone to atherosclerosis -- cardiovascular disease -- were specially bred to lack a gene called CD44, scientists saw reductions of up to 70 percent in the type of damage to blood-vessel walls associated with heart attacks and stroke.

The reduction in disease is one of the greatest effects linked to a single gene yet reported in atherosclerosis. The significance of the observation is further underscored by the fact that CD44 represents a promising target for potential therapies.

Scientists know that the development of atherosclerosis involves chronic inflammation of the vessel walls, and previous studies had implicated CD44 in other inflammatory processes.

For this reason, the researcher team, led by investigators at The Wistar Institute, sought to assess cardiovascular disease in mice without the CD44 gene. Their experiments showed that the CD44 molecule plays a central role in attracting to the vessel walls the immune-system cells that drive the inflammatory process associated with atherosclerosis.

The team's findings, published in the October issue of the Journal of Clinical Investigation, suggest that drugs that moderate CD44 activity could contribute significantly to the treatment of atherosclerosis, most likely in combination with existing therapies.

"In mice lacking the CD44 gene, we saw reductions in atherosclerotic damage to the blood vessels that were dramatic," says immunologist Ellen Puré, Ph.D., a professor at The Wistar Institute and senior author on the study. "It suggests that if we can develop drugs to interfere with CD44 or, perhaps, selected molecules with which it interacts, we may be able to make a real contribution to lowering the likelihood of heart attack and stroke in at-risk individuals."

One of the advantages of any therapies that might target CD44, Puré explains, is that, unlike other immune-system molecules involved in chronic inflammation, CD44 does not appear to be required for some of the most important normal white blood cell functions, immune surveillance and acute response to infection.

The lead author on the Journal of Clinical Investigation study is Carolyn A. Cuff, Ph.D., formerly a member of Puré's laboratory team, now at Bristol-Myers Squibb in Hopewell, NJ. The other Wistar co-authors are Ijeoma Azonobi, Sam Chun, and Christine Yeh.

Co-authors at the University of Pennsylvania School of Medicine are Devashish Kothapalli, Ph.D., Yuanming Zhang, Richard Belkin, Anthony Secreto, Richard K. Assoian, Ph.D., professor of pharmacology, and Daniel J. Rader, M.D., associate professor of medicine. In addition to her affiliation with The Wistar Institute, Puré is also a member of The Ludwig Institute for Cancer Research in New York, NY.

Funding for the research was provided by the National Institutes of Health and the American Heart Association.

[Contact: Franklin Hoke, Marion Wyce]






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