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Einstein Researchers Discover A Novel Strategy for Preventing Artery Clogging That Leads to Heart Disease

January 29, 2004 -- (Bronx, NY) -- Researchers at the Albert Einstein College of Medicine of Yeshiva University have identified a cellular protein that promotes atherosclerosis, the process that causes heart disease by narrowing coronary arteries. Therapies that inactivate this protein could offer an entirely new approach for combating heart disease, the leading cause of death among Americans.

The study was led by Drs. Philippe G. Frank and Michael P. Lisanti in the Department of Molecular Pharmacology at Einstein and appears in the January 2004 issue of Arteriosclerosis, Thrombosis, and Vascular Biology, a publication of the American Heart Association. In an accompanying editorial, Dr. William Sessa of the Yale University School of Medicine called the study’s findings “remarkable” and “provocative.”

The research involved caveolae (Latin for “small caves”), tiny infoldings that pock the surface of cells. Caveolae are especially plentiful in endothelial cells--the cells that line blood vessels--which each contain between 5,000 and 10,000 of them. The caveolae play important roles in several biological processes including endocytosis (bringing external molecules into the cell), sending signals from the cell surface to the nucleus, and regulating cholesterol levels within cells. The Einstein researchers focused on caveolin-1, the protein that is the main building block of caveolae. 

Mice that spontaneously develop atherosclerosis were bred with mice in which the gene that codes for caveolin-1 had been “knocked out.” This interbreeding yielded two types of atherosclerosis-susceptible mice: some that could still produce the caveolin-1 protein within their cells and some that could not. 

The two groups of mice were then fed a high-fat, high-cholesterol “Western” diet. (For comparison, some members of both groups also received a control diet.) After five months, blood levels of cholesterol and triglycerides (blood fats) were measured in the mice, and their aortic arteries were assessed for plaque deposits indicating atherosclerosis.

Based on blood lipids alone, things didn’t look good for the mice lacking caveolin-1: compared with their brethren with the protein, the caveolin-1-deficient mice had significantly increased levels of cholesterol and triglycerides. But despite their unfavorable lipid status, these caveolin-1-deficient mice had much healthier arteries than their counterparts. In fact, the mice lacking caveolin-1 had a startling 70 to 80 percent reduction in atherosclerotic plaque compared with mice possessing caveolin-1.

How does the absence of caveolin-1 protect vessels from developing atherosclerosis? Probably by preventing endothelial cells from swallowing up the cholesterol from the bloodstream that ultimately clogs arteries. 

“Caveolin-1 appears necessary for the normal functioning of CD36, a cell-surface receptor that pulls “bad” LDL cholesterol into endothelial cells,” says Dr. Frank. “With caveolin-1 absent, we found that the presence of CD36 on cell surfaces was reduced by 85 to 90 percent.”

Findings from this study could lead to a new and potent class of drugs for treating or even preventing atherosclerosis. “Such drugs would be targeted to the coronary arteries, where they would prevent plaque buildup by inhibiting the formation of caveolin-1,” says Dr. Lisanti.