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Blocking “Rage” Prevents Diabetic Atherosclerosis

Lead Researchers: David Stern, Ann Marie Schmidt

P&S researchers report that they have prevented the accelerated atherosclerosis associated with diabetes in mice by blocking activation of a cell-surface receptor called RAGE. Atherosclerosis is the major cause of death and disability for patients with diabetes, and people with diabetes account for more than half of all heart attacks in the United States.

The research, reported in the September 1998 issue of Nature Medicine, suggests the discovery may provide the basis for new therapeutic strategies. Currently the only treatments for atherosclerosis associated with diabetes are control of blood sugar and conventional treatments for patients without diabetes.

“Our research emphasizes a target that people didn’t consider before. RAGE looks like it is a candidate for future therapy,” says Dr. David Stern, professor of physiology and cellular biophysics and surgery. Dr. Stern and Dr. Ann Marie Schmidt, assistant professor of surgical science and of medicine, led the P&S research team.

Although controlling blood-sugar levels, reducing weight, and lowering cholesterol can help fight blood-vessel disease, atherosclerosis, the buildup of fatty plaques inside blood vessels, remains a serious problem for patients with diabetes. No matter how carefully a patient with diabetes controls blood sugar, levels are bound to rise above optimal at some point. When that occurs, the excess blood sugar reacts with proteins and lipids in a process similar to the browning of food to form molecules known as advanced glycation end products, or AGEs. In 1992, Drs. Schmidt and Stern reported the isolation of a cell-surface receptor on cells of the blood vessel wall to which the AGEs bound. They named it RAGE, for receptor for AGE.

AGEs are found throughout the bodies of patients with diabetes, while RAGE appears to be expressed primarily in diseased tissue. Drs. Stern and Schmidt thought that accelerated atherosclerosis, as well as other complications of diabetes, might be enhanced when AGEs bind to the receptor RAGE.

To test their theory, they first had to develop an animal model of advanced and accelerated atherosclerosis in diabetes. They used genetically engineered mice prone to atherosclerosis. They induced diabetes by giving the mice streptozotocin, after which they developed atherosclerosis more rapidly and severely.

To prevent the AGEs from binding to the receptor RAGE, Drs. Schmidt and Stern injected the mice with a fragment of RAGE that extends outside the cell and binds the AGEs. This fragment of RAGE is termed soluble or sRAGE. The recombinant protein sRAGE bound to AGEs, thus preventing them from activating RAGE receptors on cells of the blood vessel wall.

“We call sRAGE a decoy because it offers a false target for AGEs. It prevents AGEs from reaching cellular receptors where they can profoundly disturb cellular functions for extended periods,” says Dr. Schmidt.

The decoys worked. Atherosclerosis among the diabetic mice dropped to the levels normally seen in the non-diabetic control mice. The sRAGE in effect prevented any atherosclerosis associated with diabetes. Furthermore, it did so without any apparent side effects.

“The study shows that the AGE/RAGE connection is crucial to the development of atherosclerosis in diabetes,” says Dr. Schmidt.

sRAGE is probably too large a molecule to be easily used as a medication on a regular basis by patients with diabetes. The researchers are now working to pinpoint the precise portions of the AGE and RAGE molecules that bind to each other so they can develop low molecular weight inhibitors that will share the protective effects of sRAGE.

Applications of RAGE blockade to other complications of diabetes have already produced encouraging results for enhancing wound repair and diminishing periodontal disease in animal models of diabetes. “We hope that this work will provide the basis for a new therapeutic strategy to help our patients with diabetes,” says Dr. Stern.

The research was funded by grants from the NIH, the Juvenile Diabetes Foundation, and the surgical research fund of the Columbia-Presbyterian Department of Surgery.

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