Jan. 7, 2000 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 mechanism of action makes the peptide and its derivatives potentially attractive tools for stimulation of therapeutic angiogenesis in various diseases, including coronary artery disease and peripheral vascular disease."
Because PR39 is secreted by white blood cells known as macrophages, this newly discovered mechanism may also link two physiological processes that naturally culminate in limited angiogenesis. Scientists have believed that ischemia (or hypoxia) -- reduced amounts of oxygen due to poor blood flow because of clogged or diseased vessels -- triggers angiogenesis by turning on a key "master switch" gene that makes HIF-1alpha. Angiogenesis is also a prominent feature of tissue repair and inflammation. In this setting, it is believed to be induced by the presence of inflammatory cells, such as macrophages, which are capable of secreting angiogenic growth factors such as VEGF and FGF. For example, experimental laser therapy in the heart is believed to work because the resulting inflammation stimulates angiogenesis. Now, it appears macrophages can also induce angiogenesis through the HIF-1alpha mechanism by producing PR39-like proteins.
"Angiogenesis is the most exciting thing to happen in cardiology since bypass surgery, and this is a completely different means of inducing it," says Simons. "This study links two processes that culminate in angiogenesis, providing a better understanding of the biology. It also identifies a molecule that activates multiple growth factor pathways, which may be more potent than a single growth factor."
In other research on therapeutic angiogenesis, scientists have focused on individual growth factors that augment the body's limited natural response to grow new vessels. A number of clinical trials are currently examining therapeutic usefulness of growth factors -- mostly FGF and VEGF -- to stimulate new blood vessels in the heart and in the limbs of patients with advanced atherosclerotic disease. More than a dozen biotech and drug firms and a handful of device companies are testing different growth factors and delivery systems in hopes of eventually complementing, delaying or even replacing angioplasty and bypass surgery. The long-term safety of this approach is not known. The new study by Simons and his colleagues suggests a way to induce a robust angiogenesis by simultaneously activating multiple growth factor families and other angiogenesis related genes and to sustain this therapeutic response.
The research was funded by the National Institutes of Health, the American Heart Association, and Chiron Corporation. Beth Israel Deaconess Medical Center has patents pending for PR39 applications in angiogenesis and other fields of use, and is considering a number of licensing strategies, including a start-up company, to focus on clinical uses of the protein.
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