Eliminating enzyme dramatically reduces cardiovascular disease

How does cholesterol in our diets end up as artery-clogging plaque that can cause heart attacks and strokes? Research in animals suggests that a little-studied enzyme may play a major role – and that drugs to target it could dramatically reduce the risk of cardiovascular disease.

Lawrence Rudel, Ph.D., from Wake Forest University School of Medicine, presented new results from his research on ACAT2, a cholesterol transforming enzyme, today at the American Heart Association’s Sixth Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology in Washington, D.C.

“Our research in animals tells us that ACAT2 is a potential treatment target to protect people against heart disease,” said Rudel, a professor of and pathology (comparative medicine) at the School of Medicine, which is part of Wake Forest University Baptist Medical Center.

Cholesterol is made by the liver and also supplied through such foods as meat, fish and dairy products. According to the American Heart Association, cholesterol is needed to insulate nerves, make cell membranes and produce certain hormones. However, because the body makes enough cholesterol on its own, too much dietary cholesterol is associated with an increased risk of heart disease.

Rudel’s work focuses on an enzyme that alters the molecular structure of cholesterol so that it can be transported to the body’s cells. There are three different enzymes (ACAT1, ACAT2 and LCAT) that can change cholesterol into a form that can be more easily carried in blood.

Studies in both mice and monkeys show that cholesterol altered by ACAT2 is more likely to build up in blood vessel walls and cause atherosclerosis. In studies of genetically altered mice that do not produce ACAT2, levels of atherosclerosis are 85 percent lower than animals producing ACAT2.

“Mice without ACAT2 don’t get atherosclerosis,” said Rudel.

Recently, Rudel and colleagues confirmed these results in normal mice by using a molecule that blocks the effects of ACAT2. This study, reported for the first time today, will be followed by a pilot study in monkeys.

Rudel hopes the research will lead to a drug that can inhibit the enzyme’s production in humans. Scientists already know that humans produce ACAT2 and that women have lower levels than men. Research has shown that estrogen can lower ACAT2 production, which may explain why women are less likely than men to get heart disease during their estrogen-producing years.

“All of these findings tell us that a potential treatment for protecting against heart disease is a compound that decreases ACAT2 activity,” said Rudel.

He said that one day, it may be considered important to test how much of patients’ cholesterol was altered by ACAT2, in addition to testing their levels of high-density lipoprotein (“good”) and low-density lipoprotein (“bad”) cholesterol.

“Reducing the risk of heart disease appears to involve more than affecting the levels of good or bad cholesterol,” said Rudel.

Rudel is also studying how the three enzymes are activated to alter cholesterol. Evidence suggests that a diet high in mono-unsaturated fats, which include olive oil, nuts and nut butters, avocado and sesame seeds, may stimulate transformation by ACAT2.

In a study of monkeys, those that were fed a diet high in monounsaturated fat got just as much heart disease as monkeys that were fed saturated fat, even though their levels of “bad” cholesterol decreased.

“Monkeys eating monounsaturated fat had all of the positive risk factor changes, but they still got heart disease,” said Rudel. “What didn’t go in the right direction? We believe it may that more of the cholesterol was transformed by ACAT2.”