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Science 312 (5770): 117-121

Copyright © 2006 by the American Association for the Advancement of Science

Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome

Jennifer P. Habashi,1* Daniel P. Judge,2* Tammy M. Holm,1 Ronald D. Cohn,1 Bart L. Loeys,1 Timothy K. Cooper,1,3 Loretha Myers,1 Erin C. Klein,1 Guosheng Liu,3 Carla Calvi,2 Megan Podowski,2 Enid R. Neptune,2 Marc K. Halushka,4 Djahida Bedja,3 Kathleen Gabrielson,3 Daniel B. Rifkin,5 Luca Carta,6 Francesco Ramirez,6 David L. Huso,3 Harry C. Dietz1,2{dagger}

Abstract: Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor–ß (TGF-ß) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-ß signaling and can be prevented by TGF-ß antagonists such as TGF-ß–neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.

1 Howard Hughes Medical Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5 Departments of Cell Biology and Medicine, New York University School of Medicine, New York, NY 10016, USA.
6 Child Health Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: hdietz{at}jhmi.edu


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H. Nistala, S. Lee-Arteaga, S. Smaldone, G. Siciliano, L. Carta, R. N. Ono, G. Sengle, E. Arteaga-Solis, R. Levasseur, P. Ducy, et al. (2010)
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One step closer to personalized genomic medicine.
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Cardiovascular manifestations in men and women carrying a FBN1 mutation.
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Multimodality Imaging Reveals a Gradual Increase in Matrix Metalloproteinase Activity at Aneurysmal Lesions in Live Fibulin-4 Mice.
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Circ Cardiovasc Imaging 3, 567-577
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In Vivo Studies of Mutant Fibrillin-1 Microfibrils.
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The revised Ghent nosology for the Marfan syndrome.
B. L. Loeys, H. C. Dietz, A. C. Braverman, B. L. Callewaert, J. De Backer, R. B. Devereux, Y. Hilhorst-Hofstee, G. Jondeau, L. Faivre, D. M. Milewicz, et al. (2010)
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