Press Releases

2001 Releases

Researchers Develop Mice Resistant to Atherosclerosis

For immediate release: May 30, 2001 

Boston, MA--A team of researchers, led by Gökhan S. Hotamisligil, Associate Professor of Nutrition at the Harvard School of Public Health, has successfully generated mice resistant to atherosclerosis and has discovered an important new pathway that could be manipulated to prevent and treat the disease. Atherosclerosis is a progressive disease in which fat and cholesterol are deposited along artery walls, creating fatty lesions, plaque and obstructions which lead to an increased risk of heart attack and stroke. The study appears in the June issue of the journal Nature Medicine (http://www.nature.com/nm/)

The researchers focused on a protein called aP2 that picks up and binds lipids circulating in the blood when they enter the cells. The aP2 protein is found in adipocytes and macrophage cells. The team has already shown that the adipocyte variety is critical in diabetes and controls the action of the hormone insulin. The presence of aP2 in the macrophage has been obscure. The team determined that the aP2 protein in the macrophage plays a critical role in the development of atherosclerosis. Macrophage cells are scavengers, removing bacteria and foreign matter from blood or tissues. When exposed to low-density-lipoproteins (LDL-bad cholesterol) and fat normal macrophages became foam cells, which are bloated with fat and LDL and secrete proteins which initiate the vascular lesions and plaque development and eventually heart disease. Macrophages without aP2 were resistant to these processes.

To demonstrate the role and effects of aP2 macrophages, the researchers used a set of mice, developed in Hotamisligil’s lab, that were deficient in aP2 as well as apolipoprotein E (apoE), a protein involved in removing cholesterol and fat from the blood. Deleting only apoE allows cholesterol to remain in the mouse blood at very high levels resulting in severe atherosclerosis. However, when aP2 is also missing, these mice exhibited minimal signs of disease. Even when placed on a high fat, high cholesterol diet, mice without aP2 were protected from atherosclerotic vessel disease despite extremely high cholesterol levels. 

The researchers then designed experiments to separate the effects of aP2 in adipocytes and macrophages and tested whether these cells independently contributed to the development of diabetes and atherosclerosis. In bone-marrow transplant experiments, researchers generated mice that were aP2-deficient only in macrophages but positive in the rest of the cells of the body. The average atherosclerotic lesion area was reduced by 43 percent when compared to mice that were not transplanted with aP2-deficient macrophages. The team concluded that by acting on these two cell types, aP2 controlled the development of diabetes and atherosclerosis through distinct mechanisms. 

Individuals with obesity suffer from a dramatic increased risk for insulin resistance, diabetes, lipid abnormalities, high blood pressure and heart disease. The link between these diseases has been mysterious. "The research breaks new ground in understanding and eventually treating several important components of this cluster also known as the Metabolic Syndrome or Syndrome X," said Hotamisligil. "We have located a brand new pathway and also targeted the cell types that control the traffic of lipids in distinct ways leading to atherosclerosis; now it’s time to get them."

The study was supported by a grant from the National Institutes of Health.

The research team included members from the Departments of Medicine, Pathology and Pharmacology at the Vanderbilt University Medical Center, Nashville TN, Bristol-Myers Squibb PRI, Department of Metabolic Research and the Department of Microbiology and Immunology at the University of Louisville School of Medicine, Louisville, KY.


For further information, please contact:

Robin Herman
Office of Communications
Harvard School of Public Health
677 Huntington Avenue
Boston, MA 02115
Phone: 617-432-4752
Email: rherman@hsph.harvard.edu