BOSTON--Researchers have identified a potentially powerful tool to promote the growth of new blood vessels in the heart to replace blocked ones. The discovery may lead to a new treatment for people with coronary artery disease or peripheral vascular disease. It also links for the first time two biological processes - inflammation and hypoxia - that normally trigger some new blood vessel growth in the body

Cardiologist Michael Simons, MD, director of the Angiogenesis Research Center at Beth Israel Deaconess Medical Center, and his colleagues have found that a naturally occurring antibacterial peptide called PR39 encourages angiogenesis. In mice studies, injecting PR39 into the myocardium resulted in a three-fold increase in vessel growth, according to a paper published in the Jan. 2000 issue of Nature Medicine. Most importantly, says Simons, the newly formed vessels were fully functional.

PR39 achieves this affect by a new mechanism. The peptide blocks the degradation of a "master switch" transcription factor. Known as hypoxia-inducible factor (HIF)-1alpha, it turns on expression of multiple angiogenesis-related genes, including genes for the growth factor VEGF and its receptors. Also, PR39 stimulates the expression of receptors for another family of potent inducers of angiogenesis, fibroblast growth factors (FGF). A combination of VEGF and FGF has been shown to be much more effective in inducing angiogenesis than either group alone, says Simons, also an associate professor of medicine at Harvard Medical School.

The peptide PR39 promotes angiogenesis by blocking the cell's central protein-degradation factory known as a proteasome, an organized collection of cellular proteases, which would otherwise break down HIF-1alpha. "Unlike the other available proteasome inhibitors, PR39 appears to be fairly selective for HIF-1alpha, thereby likely minimizing side effects typically observed with the use of proteasome inhibitors," says Simons. "This unique mechani
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Contact: Carol Cruzan Morton
cmorton@caregroup.harvard.edu
617-975-6150
Beth Israel Deaconess Medical Center
4-Jan-2000