Jan 10, 2004 By: yunews
Jan 10, 2004 -- Researchers at the Albert Einstein College of Medicine 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鈥檚 findings 鈥渞emarkable鈥 and 鈥減rovocative.鈥
The research involved caveolae (Latin for 鈥渟mall caves鈥), 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 鈥渒nocked out.鈥 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 鈥淲estern鈥 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鈥檛 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.
鈥淐aveolin-1 appears necessary for the normal functioning of CD36, a cell-surface receptor that pulls 鈥渂ad鈥 LDL cholesterol into endothelial cells,鈥 says Dr. Frank. 鈥淲ith caveolin-1 absent, we found that the presence of CD36 on cell surfaces was reduced by 85 to 90 percent.鈥
Findings from this study could lead to a new and potent class of drugs for treating or even preventing atherosclerosis. 鈥淪uch drugs would be targeted to the coronary arteries, where they would prevent plaque buildup by inhibiting the formation of caveolin-1,鈥 says Dr. Lisanti.
