Jan. 24, 2003 Philadelphia, PA -– Scientists have found a new way in which exercise may protect against heart disease. Increased blood flow can mimic the powerful anti-inflammatory actions of certain glucocorticoid steroid drugs, according to researchers at the University of Pennsylvania's Institute for Medicine and Engineering. The researchers discovered that an increase in shear stress – the drag force exerted by blood flowing over endothelial cells that line blood vessels – results in the same sort of anti-inflammatory events normally associated with high doses of steroids.
Their findings will be presented in the January 24th online edition of Circulation Research: Journal of the American Heart Association, followed by the print edition of the journal on February 21st.
"Inflammation in blood vessels has been linked to atherosclerosis, a hardening of the arteries, and here we see how the physical force of blood flow can cause cells to produce their own anti-inflammatory response," said Scott L. Diamond, PhD, director of the Penn's Biotechnology Program and a professor of chemical and biomolecular engineering at Penn's School of Engineering and Applied Science. "Conceivably, exercise provides the localized benefits of glucocorticoids – just as potent as high doses of steroids, yet without all the systemic side effects of taking the drugs themselves."
"Perhaps this is a natural way in which exercise helps protect the vessels, by stimulating an anti-inflammatory program when the vessels are exposed to elevated blood flow. We're not talking about running a marathon here, we're just talking about getting the blood moving at high arterial levels," said Diamond.
It is the first direct evidence that the mechanical effects of blood flow have anti-inflammatory properties. According to their findings, shear stress can activate glucocorticoid receptors (GR) to enter the nucleus of the cells, an event normally triggered by glucocorticoid steroids. Once inside the nucleus, the activated GR binds to the DNA to turn genes on and off.
Diamond and his colleagues studied the effect of shear stress on glucocorticoid receptors in endothelial cells grown in culture by recreating in the laboratory the flow environment of the large arteries. Sustained shear stress – in the form of a steady stream of liquid flowing across the cell culture – caused GRs to move into the cell nuclei where they triggered the transcription of a specially designed reporter gene. In fact, the effect of shear stress alone had the same effect as dexamethasone, a glucocorticoid steroid used to treat inflammation.
The researchers helped confirmed these findings in vivo by examining a portion of the human mammary artery and discovering that the blood flow had indeed caused GR to be localized in the nucleus of the endothelial cells. While the anti-inflammatory effects of exercise training has yet to be documented in vivo, Diamond believes the findings are applicable to living blood vessels.
"Think of blood flow as a stream: whenever a stream branches off you get small areas of recirculation eddies or pools of stagnant water. These same situations of disturbed flow irritate the endothelium. When blood vessels branch off, all the arterial flotsam – fats and activated blood cells – can clump and stick at these hot spots for atherosclerotic plaque formation," said Diamond. "Perhaps, elevated blood flow may alter these disease prone regions to relieve some of the localized inflammation."
### The Institute for Medicine and Engineering was established jointly by Penn's School of Medicine and Penn's School of Engineering and Applied Science. Its focus is on interdisciplinary research and education fundamental to the application of advances in the treatment of disease.
Other Penn researchers involved in this study include Julie Y. Ji and Huiyan Jing of the Institute for Medicine and Engineering. Funding for this research comes from the National Institutes of Health.
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