June 8, 2001

Protein links heart disease, diabetes

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Dr. MacRae F. Linton

Protein links heart disease, diabetes

Dr. Sergio Fazio

Dr. Sergio Fazio

Vanderbilt researchers have identified a protein’s key role in the formation of atherosclerosis, the leading cause of death in the United States, and helped establish a link between heart disease and diabetes. Their findings, published in the current issue of Nature Medicine, could lead to targeted therapies to prevent both diseases.

The protein, aP2, had previously been linked in mice to insulin resistance and hypertriglyerceridemia, two risk factors for heart disease in a cluster of symptoms – others include high blood pressure, abdominal obesity and premature atherosclerosis – known as the metabolic syndrome.

“That alone suggested a potential role (for aP2) in atherosclerosis,” said Dr. MacRae F. Linton, associate professor of Medicine in Cardiology and principal investigator of the study.

Also, aP2 is known to be expressed by fat cells and macrophages. In macrophages, the protein promotes the formation of foam cells, cholesterol-loaded macrophages present in the initial events of atherosclerosis. That role, Linton said, is independent of its effects on insulin resistance or increasing plasma lipids.

“That made us wonder if macrophages’ expression of aP2 has a role independent of fat cells’ production of aP2,” Linton said.

To test aP2’s role in atherosclerosis, the buildup of plaque in arteries that restricts blood flow to the heart, Linton and his colleagues used mice genetically engineered to be at risk for the disorder. Through bone marrow transplants, they disabled the mice’s macrophages from producing aP2.

When the mice were fed a regular diet, one that would not change insulin resistance or plasma lipids, they “were highly protected against atherosclerosis in the absence of significant changes in lipid metabolism or insulin sensitivity,” Linton said.

Moreover, the study showed that mice lacking aP2 have macrophages that are less likely to accumulate cholesterol and that secrete fewer inflammatory cytokines, Linton said.

Collaborating on the study, funded by a grant from the National Heart, Lung and Blood Institute, were Dr. Sergio Fazio, associate professor of Medicine and Pathology and co-director with Linton of the Atherosclerosis Research Unit; Dr. Jeffrey Boord, a post-doctoral fellow in Endocrinology; and Dr. Gokhan Hotamisligil and other researchers at the Harvard School of Public Health.

The study also is the first to link aP2 to both atherosclerosis and insulin resistance insulin-resistance diabetes, Linton said.

“Seventy-five percent of all hospital admissions of diabetics are due to atherosclerosis,” Boord said. “This study is very important work in uncovering the mechanisms responsible for atherosclerosis in our diabetic patients.”

The findings establish aP2 as a “potential therapeutic target for insulin resistance and atherosclerosis,” Linton said.

In the mid-1990s, Hotamisligil found that aP2 had a role in insulin resistance by showing that mice lacking aP2 were more insulin sensitive. People with diabetes are now known to have the same risk for heart attack as nondiabetic people with coronary artery disease. And while insulin resistance is believed to be key in the metabolic syndrome, the molecular basis for the metabolic syndrome is largely unknown, Linton said.

“Our results are interesting because they indicate that aP2 links several features of the metabolic syndrome with atherosclerosis,” he said.