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New Molecular Trigger Described for Hypertension, Diabetes
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Rogue versions of enzymes known as proteases roam the body, clipping off working segments of the receptors that allow insulin to enter cells and do its job, according to a report in the June 30 online issue of Hypertension.
That uncontrolled enzymatic activity also reduces the immune system's response to infection and raises blood pressure, the report noted.
"We are describing a new mechanism for disease and injury to the body," said study author Frank DeLano, a research scientist with the department of bioengineering at the University of California, San Diego. "It is an idea that hasn't been presented before. If we apply a protease inhibitor, we can prevent the damage we see in laboratory animals."
DeLano and his collaborator, Geert Schmid-Schonbein, a professor of bioengineering at UCSD, have been working with a widely used laboratory model of disease, a rat bred to have high blood pressure.
They have found that proteases, whose function is to clear away molecular debris, can go awry and split apart a number of different cell wall receptors. If insulin receptors are damaged, normal metabolism of glucose is not possible, and diabetes can be the result. Proteases can also damage receptors that are vital for the functioning of infection-fighting leukocytes.
The researchers also found that protein receptors on the surface of cells are clipped off as the rats develop high blood pressure. "Many receptors in blood vessels cause them to relax," DeLano said. "Many proteases we see in the animals cleave receptors responsible for relaxation." Giving the rats doxycycline, an antibiotic that is also a protease inhibitor, brought down their blood pressure and restored normal immune system function.
The proteases that cause the damage leak out of the intestine, DeLano said. "The mechanism is a leaky or permeable intestine," he said. "We call it leaky gut syndrome."
A major next step will be to show that the protease damage seen in laboratory rats occurs in humans. "We will have to do human trials," DeLano said. "We are working with other researchers on human trials."
"This is really an important observation," said H. Glenn Bohlen, a professor of cellular and integrative physiology at Indiana University Medical School, who wrote an accompanying editorial. "It ties in information that high blood pressure and insulin resistance have the same cause, damage to receptors."
The function of proteases in rats and humans is the same, so what has been seen in the laboratory rats likely occurs in people. "It probably happens in humans on a different scale," Bohlen said. "Rats live at a different metabolic rate, much faster than in people."
The newly reported studies might also help explain why antioxidants such as vitamins C and E help against inflammation, he said.
"The next approach probably would be to treat an inflammatory state," Bohlen said. "There is something going on that we can interact with. There are many commercially available methods for blocking proteases."
SOURCES: Frank DeLano, Ph.D, research scientist, department of bioengineering, University of California, San Diego; H. Glenn Bohlen, Ph.D, professor, cellular and integrative physiology, Indiana University, Indianapolis; June 30, 2008, Hypertension, online
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