Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.
Journal: 2006/April - Science
ISSN: 1095-9203
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-beta (TGF-beta) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-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.
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Science 312(5770): 117-121

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

+11 authors
Howard Hughes Medical Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Departments of Cell Biology and Medicine, New York University School of Medicine, New York, NY 10016, USA.
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: ude.imhj@zteidh

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.

Abstract

Footnotes

Supporting Online Material www.sciencemag.org/cgi/content/full/312/5770/117/DC1 Materials and Methods Figs. S1 to S4 References

Footnotes

References and Notes

References and Notes

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  • 32. We thank K. Khan for expert technical assistance. Supported by the NIH (H.C.D., D.P.J., D.L.H., D.B.R., F.R.), the Smilow Center for Marfan Syndrome Research (H.C.D.), the National Marfan Foundation (H.C.D., D.P.J.), the Howard Hughes Medical Institute (H.C.D.), the Victor A. McKusick Endowment (H.C.D.), and the Dana and Albert “Cubby” Broccoli Center for Aortic Diseases (D.P.J.). All protocols for mouse treatment were approved by the Animal Care and Use Committee of the Johns Hopkins University School of Medicine.
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