UW News

July 29, 2002

Chemical used to break up blood clots may also cause narrowing of blood vessels, a major problem in heart disease

Research into gene therapy shows that a substance used to treat blood clots may also be involved in the process by which arteries become narrowed and reduce the flow of blood to vital organs.

In experiments described in this week’s Proceedings of the National Academy of Sciences, Dr. David Dichek, professor and associate director for research in cardiology in the Department of Medicine in the University of Washington School of Medicine, and his colleagues showed that elevated levels of urokinase-type plasminogen activator, referred to as urokinase, can cause constriction of blood vessels. Dichek was trying to determine if genetic engineering of blood vessels to express higher levels of urokinase would prevent thrombosis, or clot formation, in situations where atherosclerosis already existed.

“We have been developing gene therapy for treatment of thrombosis for many years in our laboratory, and one of our ideas was to use gene therapy to over-express urokinase in the walls of blood vessels to prevent them from forming blood clots, since urokinase is effective in removing them,” Dichek said. “But before pursuing this therapy, we needed to know whether this could cause harm. This finding leads us away from expressing increased amounts of urokinase in blood vessels in order to prevent thrombosis.”

Dichek’s previous studies had looked at the effect of genetic over-expression of urokinase during an hour-long experiment. This latest study looked at the result of two weeks of increased expression of urokinase on the carotid arteries of cholesterol-fed rabbits. By four weeks after the gene transfer, the inner lining of the rabbits’ artery walls had thickened by about 70 percent.

“We have known for many years that urokinase was present in the atherosclerotic blood vessel wall, but we have not been able to tell whether it was contributing to the disease or preventing it. This is the first study to indicate that urokinase is not a benign presence in the blood vessels of people suffering from atherosclerosis. We now need to understand the pathways by which urokinase is promoting disease, and that is the next step in our research,” Dichek said. “Then we’ll see if those pathways are reasonable targets for interference, perhaps with drugs or gene therapy that will prevent atherosclerosis.”

Dichek does not regard this unforeseen study result as a setback in his efforts to prevent or break up thrombosis, a frequent cause of cardiac events: “It simply points us in a different direction.”

“This type of result is a good example of how by doing research into potential gene therapies, we can also develop a better understanding of basic biology and the role of genes in disease processes,” Dichek said. “This understanding allows us to design better therapies.”