Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome

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

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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.

Original languageEnglish (US)
Pages (from-to)117-121
Number of pages5
JournalScience
Volume312
Issue number5770
DOIs
StatePublished - Apr 7 2006

All Science Journal Classification (ASJC) codes

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    Habashi, J. P., Judge, D. P., Holm, T. M., Cohn, R. D., Loeys, B. L., Cooper, T. K., Myers, L., Klein, E. C., Liu, G., Calvi, C., Podowski, M., Neptune, E. R., Halushka, M. K., Bedja, D., Gabrielson, K., Rifkin, D. B., Carta, L., Ramirez, F., Huso, D. L., & Dietz, H. C. (2006). Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science, 312(5770), 117-121. https://doi.org/10.1126/science.1124287