Experimental lupus drug may also work against atherosclerosis

A drug that reduces symptoms of systemic lupus in mice may turn out to be effective against hardening of the arteries and thus prevent heart attacks, according to two poster presentations today at the American College of Rheumatology meeting in San Antonio.

Nilamadhab Mishra, M.D., of Wake Forest University Baptist Medical Center, said the drug, called Trichostatin A or TSA, “may have a therapeutic benefit in atherosclerosis,” which causes coronary artery disease by blocking key arteries, leading to death and disability. Mishra, assistant professor of internal medicine – rheumatology, and his colleagues tested TSA on experimental mice that were bred to lack a significant natural protection against atherosclerosis. For 12 weeks, these mice were fed a diet that was both high in cholesterol and in which 10 percent of calories came from palm oil, one of the vegetable oils most likely to cause atherosclerosis. In addition to the coronary arteries, atherosclerosis also occurred in the aortic arch, part of one of the body’s main blood vessels.

When Mishra compared the mice given TSA with mice given an inert substance, the amount of atherosclerosis deposited in the aortic arch was cut in half. The TSA-treated mice also had a reduction in total and free cholesterol levels in the abdominal aorta, the lower portion of the aorta, the body’s largest blood vessel.

These mice had a three-fold reduction in the gathering of macrophages, a type of white blood cell. Scientists increasingly are viewing the depositing of cholesterol in the walls of arteries as an inflammatory reaction that attracts the disease-fighting macrophages, which then become incorporated with cholesterol deposits to become plaque.

“The recognition of atherosclerosis as an inflammatory disease raised the question of whether anti-inflammatory drugs might decrease this disease process,” said Mishra, who noted that TSA is not only an anti-cancer and anti-lupus drug, but also an anti-inflammatory agent. TSA treatment changed the composition of the atherosclerotic deposit in a way that may lead to plaque stability, so pieces don’t break off so easily. The breaking off of plaques, which then can lodge elsewhere in already narrowed arteries, is a key mechanism for heart attacks and strokes.

Mishra got similar results when he tested TSA on another type of experimental mice that are also prone to atherosclerosis. He said a gene called CD154 causes both atherosclerosis and lupus. “This drug inhibits both.”

Mishra’s team included John S. Parks, Ph.D., professor of pathology (comparative medicine), Anh Nghiem, B.S., Elene Boudyguina, B.S., and Doris R. Brown, Ph.D., all at Wake Forest Baptist, and Samantha Laclair. B.S., and Uwe Schonbeck, Ph.D., of Brigham and Women’s Hospital of Harvard Medical School in Boston.