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Spotlight on Research for 2006
June 2006 (historical)
Hypertension Drug Proves Promising for Deadly Complication of Marfan Syndrome in Mouse Model
The popular antihypertensive medication losartan may be useful for more than lowering high blood pressure, suggests a recent study supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). In laboratory mice, at least, the medication prevents a deadly complication of the connective tissue disorder Marfan syndrome: aortic rupture.
The study was headed by Harry (Hal) Deitz, M.D., an investigator in the Howard Hughes Medical Institute and director of the Smilow Center for Marfan Syndrome Research at the Johns Hopkins University School of Medicine. Other involved researchers were from the Robert Wood Johnson Medical School and the New York University School of Medicine.
Caused by a mutation in the gene that encodes for fibrillin-1 (a protein component of connective tissue), Marfan syndrome can affect the bones, skin, eyes, heart and blood vessels, nervous system and lungs. The syndrome can prove fatal if it weakens the aorta (the largest artery of the body) to the point of rupture.
Traditionally, scientists have believed that fibrillin-1 played primarily a structural role in connective tissue disease, and that the only way to prevent aortic aneurysm or rupture in Marfan patients was to surgically replace the aorta. But recent findings about the role of fibrillin have not only offered new insight into the cause of aortic rupture in Marfan syndrome, but also have offered clues to simpler, less invasive ways to prevent it.
Studies with mice engineered to make low amounts of fibrillin-1 that had lung damage similar to that seen in Marfan syndrome have shown that the damage was linked to a protein called transforming growth factor-beta (TGF-β) that is overactive in people (and mice) with Marfan syndrome. They also found that giving the mice antibodies that bound TGF-β (rendering it inactive) prevented lung and heart valve abnormalities.
Looking for an easier way to slow down TGF-β, the researchers decided to try losartan, which is known to suppress TGF-β in animal models of other conditions. When they gave the drug to specially engineered mice, which were already experiencing changes to their aortas, the results were dramatic, says geneticist Francesco Ramirez, Ph.D., of the Robert Wood Johnson Medical School, one of the key researchers and principal investigator of the consortium grant funded by NIAMS that has supported these studies. After six months, the aortas of the Marfan-affected mice were indistinguishable from those of healthy mice, meaning losartan had not only stopped further damage but had reversed damage that had already occurred.
While the popular antihypertensive has not yet been tested for this purpose in people, that is the next step, says Ramirez. "Losartan is currently in widespread clinical use for the treatment of hypertension in both adults and children," he remarks. "Thanks to Hal's findings in mice and the well-documented safety profile of this drug in all age groups, we believe that a prospective trial in patients with Marfan syndrome is indicated."
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.
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Habashi JP, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-121.