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

Author:

Habashi Jennifer P.12345,Judge Daniel P.12345,Holm Tammy M.12345,Cohn Ronald D.12345,Loeys Bart L.12345,Cooper Timothy K.12345,Myers Loretha12345,Klein Erin C.12345,Liu Guosheng12345,Calvi Carla12345,Podowski Megan12345,Neptune Enid R.12345,Halushka Marc K.12345,Bedja Djahida12345,Gabrielson Kathleen12345,Rifkin Daniel B.12345,Carta Luca12345,Ramirez Francesco12345,Huso David L.12345,Dietz Harry C.12345

Affiliation:

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.

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–β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β–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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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