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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,1Ronald D. Cohn,1Bart L. Loeys,1Timothy K. Cooper,1,3Loretha Myers,1Erin C. Klein,1Guosheng Liu,3Carla Calvi,2Megan Podowski,2Enid R. Neptune,2Marc K. Halushka,4Djahida Bedja,3Kathleen Gabrielson,3Daniel B. Rifkin,5Luca Carta,6Francesco Ramirez,6David L. Huso,3Harry C. Dietz1,2
Aortic aneurysm and dissection are manifestations of Marfansyndrome (MFS), a disorder caused by mutations in the gene thatencodes fibrillin-1. Selected manifestations of MFS reflectexcessive signaling by the transforming growth factor–ß(TGF-ß) family of cytokines. We show that aortic aneurysmin a mouse model of MFS is associated with increased TGF-ßsignaling and can be prevented by TGF-ß antagonistssuch as TGF-ß–neutralizing antibody or the angiotensinII type 1 receptor (AT1) blocker, losartan. AT1 antagonism alsopartially reversed noncardiovascular manifestations of MFS,including impaired alveolar septation. These data suggest thatlosartan, a drug already in clinical use for hypertension, meritsinvestigation as a therapeutic strategy for patients with MFSand has the potential to prevent the major life-threateningmanifestation 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.
To whom correspondence should be addressed. E-mail: hdietz{at}jhmi.edu
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