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Spotlight on Research 2011
Scientists Identify Potential Drug Target, Molecular Pathway, for Marfan Syndrome
A Johns Hopkins University research team studying the Marfan syndrome drug losartan has found a new therapy target for the disease, which is characterized by potentially fatal flaws in the bodyís connective tissue. The target, a protein called ERK, is involved in a cell signaling process that can result in thoracic aortic aneurysm and dissection, an often fatal Marfan complication in which the heartís aorta weakens and ruptures. The team, led by Harry Dietz, M.D., found that inhibiting the activity of ERK could stop aortic weakening in a mouse model of Marfan syndrome. In a separate study, they also discovered why losartan is so much more effective than a similar molecule, ACEi (angiostatin converting enzyme inhibitor), in treating Marfan syndrome. Their work, supported, in part, by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), advances understanding about the disease and its molecular mechanisms. The two studies were reported in Science.
Marfan syndrome is a heritable condition that affects connective tissue, which holds the body together and provides a framework for growth and development. It is caused by a defect in the gene that determines the structure of fibrillin-1, a protein that is an important part of connective tissue. Marfan syndrome can affect many body systems, including the skeleton, eyes, heart and blood vessels, nervous system, skin and lungs. Beginning in 2003, Dr. Dietz showed that a cellular signaling molecule called TGFβ (transforming growth factor beta) contributes to many of the physical features of Marfan syndrome, and that blocking TGFβ could reduce or prevent important aspects of the disease in a mouse model of Marfan syndrome. Later studies in mice demonstrated that losartan—a common blood pressure medication that can block TGFβ—was successful in helping to manage the disease. Dr. Dietzís new losartan studies have shed more light on the disease process and the potential for other Marfan treatments.
TGFβ signals travel through two different pathways in the cell: a standard one involving proteins called Smads, and an alternate one involving the protein ERK. The Dietz research team showed that—contrary to prior thinking—the ERK TGFβ pathway was the primary determinant of aortic weakening in Marfan syndrome. Following this new lead, the scientists proceeded to show that inhibiting ERK activity stopped the aortic weakening in a mouse model of the disease.
The team also uncovered the mechanism that makes losartan treatment more successful in Marfan mice than a similar class of drugs, ACEi. While both classes of drugs suppress TGFβ, ACEi only blocked Smad activity, while losartan blocked both Smad and ERK signaling. This blockade of ERK was essential to inhibit abnormal aortic growth. The teamís work reveals yet more information about the intricate molecular pathways that are part of the Marfan syndrome puzzle.
Partial support for these studies was also provided by the Howard Hughes Medical Institute, the Smilow Center for Marfan Syndrome Research, and the National Marfan Foundation.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Servicesí National Institutes of Health (NIH), 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 the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.
Holm TM, Habashi JP, Doyle JJ, Bedja D, Chen Y, van Erp C, Lindsay ME, Kim D, Schoenhoff F, Cohn RD, Loeys BL, Thomas CJ, Patnaik S, Marugan JJ, Judge DP, Dietz HC. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science. 2011 Apr 15; 332(6027):358-61. PMID: 21493862.
Habashi JP, Doyle JJ, Holm TM, Aziz H, Schoenhoff F, Bedja D, Chen Y, Modiri AN, Judge DP, Dietz HC. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. 2011 Apr 15; 332(6027):361-65. PMID: 21493863.