image: This image of atherosclerotic plaque shows the accumulation of macrophages in red. The movement of these cholesterol-laden, coronary artery disease-causing cells in and out of artery plaque was tracked by researchers using green fluorescent beads which can be seen within the red-stained cells. view more
Credit: NYU Langone Medical Center
A new study by NYU Langone Medical Center researchers identified a new culprit that leads to atherosclerosis, the accumulation of fat and cholesterol that hardens into plaque and narrows arteries. The research, published online by Nature Immunology on January 8, 2012, explains why cholesterol-laden, coronary artery disease-causing cells called macrophages, accumulate in artery plaques.
"We have discovered that macrophages that accumulate in plaques secrete a molecule called netrin-1," said Kathryn J. Moore, PhD, senior author of the study and associate professor in the Departments of Medicine and Cell Biology at NYU Langone Medical Center. "Our study shows that netrin-1 blocks the normal migration of macrophages out of arteries, causing these immune cells to accumulate and promote the progression of atherosclerosis."
Artery plaques that break off causing vessel blockages, or potentially fatal heart attacks and strokes are known to have high macrophage cell content. Atherosclerosis is fueled by the presence of these cholesterol-laden macrophages in the artery wall. Typically, the immune system sends macrophages to clean up cholesterol deposits in arteries, but once they fill up with the unhealthy form of cholesterol they get stuck in the arteries, triggering the body's inflammatory response. The bloated macrophages then become major components of plaque lining artery walls. Until now, the mechanism by which macrophages become trapped has remained unknown.
In this new study, researchers show why macrophages remain in artery plaques leading to atherosclerosis. Netrin-1 promotes atherosclerosis by retaining macrophages in the artery wall. In fact, netrin-1 signals macrophages to stop migrating and as a result these cells accumulate within the plaque. In addition, study experiments show, genetically deleting netrin-1 can minimize atherosclerosis, reduce the level of macrophages in plaque and promote the migration of macrophages from plaques.
In the study researchers used a florescent tracking technique to label and monitor the movement of macrophage cells in and out of plaques. This experiment showed how macrophages were immobilized and retained in plaque by netrin-1 expression and also demonstrated macrophage emigration from plaque after the deletion of netrin-1.
"Our study identifies netrin-1 as a novel target for future therapeutic intervention for the treatment of atherosclerosis and cardiovascular disease," said Janine M. van Gils, PhD, lead author of the study and a post-doctoral researcher in the Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine at NYU Langone Medical Center. "This discovery provides new clues to help reduce the amount of plaque in arteries and the threat of atherosclerosis, a major cause of mortality in Western countries. The development of a new strategy to diminish macrophage accumulation in plaque offers great promise to reducing the occurrence of fatal cardiac events."
The study was a collaboration between NYU School of Medicine, Massachusetts General Hospital, Harvard Medical School, Federal University of Monas Gerais, Belo Horizonte in Brazil and the University of Washington. The study was supported by the American Heart Association, the National Institutes of Health, the Heart and Stroke Foundation of Canada and the Conselho Nacional Desenvolvimento Cientifico e Tecnologico.
About NYU Langone Medical Center
NYU Langone Medical Center, a world-class, patient-centered, integrated, academic medical center, is one on the nation's premier centers for excellence in clinical care, biomedical research and medical education. Located in the heart of Manhattan, NYU Langone is composed of three hospitals – Tisch Hospital, its flagship acute care facility; the Rusk Institute of Rehabilitation Medicine, the world's first university-affiliated facility devoted entirely to rehabilitation medicine; and the Hospital for Joint Diseases, one of only five hospitals in the nation dedicated to orthopaedics and rheumatology – plus the NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The medical center's tri-fold mission to serve, teach and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education and research. For more information, go to www.NYULMC.org.
Journal
Nature Immunology