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

doi:10.1126/science.1124287

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 language	English (US)
Pages (from-to)	117-121
Number of pages	5
Journal	Science
Volume	312
Issue number	5770
DOIs	https://doi.org/10.1126/science.1124287
State	Published - Apr 7 2006

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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

Habashi, JP, Judge, DP, Holm, TM, Cohn, RD, Loeys, BL, Cooper, TK, Myers, L, Klein, EC, Liu, G, Calvi, C, Podowski, M, Neptune, ER, Halushka, MK, Bedja, D, Gabrielson, K, Rifkin, DB, Carta, L, Ramirez, F, Huso, DL & Dietz, HC 2006, 'Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome', Science, vol. 312, no. 5770, pp. 117-121. https://doi.org/10.1126/science.1124287

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

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.",

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

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AU - Cooper, Timothy K.

AU - Myers, Loretha

AU - Klein, Erin C.

AU - Liu, Guosheng

AU - Calvi, Carla

AU - Podowski, Megan

AU - Neptune, Enid R.

AU - Halushka, Marc K.

AU - Bedja, Djahida

AU - Gabrielson, Kathleen

AU - Rifkin, Daniel B.

AU - Carta, Luca

AU - Ramirez, Francesco

AU - Huso, David L.

AU - Dietz, Harry C.

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AB - 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.

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

Abstract

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