August 24, 2005
For Immediate Release
Contact: Mary Jane Gore
434-924-9241
mjgore@virginia.edu

UVa Researchers Find a Treatment that Potentially Could Reduce Heart Disease in the Metabolic Syndrome

The metabolic syndrome, a dangerous combination of pre-diabetes and heart-disease factors that affects up to 25 percent of the population, is a chief culprit in American illness. As part of an effort to eventually treat this debilitating syndrome, researchers at the University of Virginia have studied biological pathways that affect inflammation in blood vessels that could lead to severe heart disease.

Their findings, published in the Aug. 23 issue of the American Journal of Physiology – Endocrinology and Metabolism, include promising results with lisofylline, a novel anti-inflammatory agent that blocked a detrimental genetic pathway and significantly reduced damage to blood vessels. If the results can be translated to humans, agents that reduce chronic inflammation may help keep blood vessels free of atherosclerosis and reduce cardiovascular disease in people who have metabolic syndrome and possibly diabetes.

 So far, UVa researchers have studied obese rats that mimicked the symptoms of metabolic syndrome: the rats have increased insulin and triglyceride levels without a marked increase in glucose. Researchers compared the biology of the obese rats to that of lean rats. All rats received a procedure similar to a balloon angioplasty that is used to open blood vessels.

Two substances that mediate inflammation in the vessels were studied: 12-lipoxygenase (12-LO) and a factor that turns on genes, called signal transducer and activator of transcription 4 (STAT 4).

Researchers found that the obese rats had a 7-fold increase in 12-LO levels compared to lean rats by day 30 after the balloon procedure, indicating more inflammation in these animals. Staining of the active form of STAT 4 in lesions from obese rats was also increased compared to that of lean rats. This means that obese rats suffered more inflammation and more damage to the lining of their blood vessels after the balloon procedure, and new cells built up quickly in the vessel lining compared with the rate in lean rats. This process of building up new cells in the vessel lining is similar to the build-up of fatty plaque during   atherosclerosis, the process that blocks arteries in humans.

Because the STAT-4 pathway involves switching on genes that turn on detrimental activity, targeting and shutting off this switch should minimize damage to the inside of blood vessels, said Jerry Nadler, M.D., chief of the UVa Division of Endocrinology and Metabolism and an author of the study. “We then used lisofylline (LSF) in the obese rats, which markedly reduced the formation of new cells in the lining of the vessels in obese rats.” LSF also reduced monocyte/macrophage infiltration into the vessel wall and activation of STAT 4.

“This was a very dramatic response,” Nadler explains. “It’s clear that LSF affects inflammation levels and prevents the damaging STAT-4 pathway from becoming active.” The next step will be studying these parameters in a pig model. If this study is successful, Nadler says, researchers may be able to move forward in the quest to block vessel damage in insulin-resistant people.

Nadler and colleagues hope to more fully understand and characterize the inflammatory molecules and signals leading to heart disease in the metabolic syndrome.

This work is supported by a Program Project Grant from the National Heart, Lung and Blood Institute, part of the National Institutes of Health.

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