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New leads for fighting heart disease
Studies in mice push scientists to rethink how inflammation contributes to unhealthy arteries
Every morning, thousands of Americans begin their day by taking a tiny pill that lowers their very big risk for a heart attack. The pill — one of the so-called “statin” drugs — prevents heart attacks by reducing high levels of the “bad” form of cholesterol circulating in their blood stream.
But cholesterol levels, like exercise, diet and smoking, do not tell the whole story. Many people with heart disease have high blood levels of C-reactive protein and other substances in their blood vessels which are produced by the immune system as a result of inflammation that occurs in response to the accumulation of fatty plaque deposits during the early stages of the disease. Some researchers have proposed that drugs should be developed to lower these inflammatory factors in the blood stream, in the same way that statins reduce cholesterol.
However, recent research by Jan Breslow, Frederick Henry Leonhardt Professor and head of the Laboratory of Biochemical Genetics and Metabolism, and Susanne Idel, a postdoctoral associate in Breslow’s lab, indicate that turning off one major pathway that causes this inflammatory response may actually worsen heart disease, at least in the laboratory mice they studied.
In a study just published in the Proceedings of the National Academy of Sciences, they report that a genetic pathway previously believed to contribute to heart disease may actually have a protective effect. If confirmed, the results could suggest new treatment approaches against heart disease, the number one killer of adult men and women in the United States.
The genetic pathway Breslow and Idel studied is known as the Nuclear Factor Kappa-B (NFkB) pathway. “The idea that NFkB has an anti-atherosclerotic effect is controversial,” says Idel. “But, if it were true that the pathway had only harmful effects, then turning it off should have protected the mice. This is not what we have observed.”
In fact, when Idel and Breslow examined the genetic differences in two separate strains of mice, they found more severe atherosclerosis in the animals with genes that turned off the pathway most effectively.
“NFkB does turn on inflammatory genes,” concludes Idel, “but you can’t disregard that it also turns on other genes that may ameliorate atherosclerosis. There is still much that is unknown about the genetics of heart disease, but A20 and the NFkB pathway offer promising leads worthy of more study.”
“Right now, the main ways we have to prevent heart disease relate to cholesterol, blood pressure and other risk factors for heart attack,” says Idel. “In the long term, our hope is that a more complex understanding of the
genetics involved will give us new tools for treating heart disease.”

December 12, 2003



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