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

Research output: Contribution to journalArticle

1155 Citations (Scopus)

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

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Marfan Syndrome
Losartan
Aortic Aneurysm
Transforming Growth Factors
Angiotensin II Type 1 Receptor Blockers
Neutralizing Antibodies
Dissection
Cytokines
Hypertension
Mutation
Pharmaceutical Preparations
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Habashi, J. P., Judge, D. P., Holm, T. M., Cohn, R. D., Loeys, B. L., Cooper, T. K., ... 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, Jennifer P. ; Judge, Daniel P. ; Holm, Tammy M. ; Cohn, Ronald D. ; Loeys, Bart L. ; Cooper, Timothy K. ; Myers, Loretha ; Klein, Erin C. ; Liu, Guosheng ; Calvi, Carla ; Podowski, Megan ; Neptune, Enid R. ; Halushka, Marc K. ; Bedja, Djahida ; Gabrielson, Kathleen ; Rifkin, Daniel B. ; Carta, Luca ; Ramirez, Francesco ; Huso, David L. ; Dietz, Harry C. / Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. In: Science. 2006 ; Vol. 312, No. 5770. pp. 117-121.
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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.",
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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

Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. / Habashi, Jennifer P.; Judge, Daniel P.; Holm, Tammy M.; Cohn, Ronald D.; Loeys, Bart L.; Cooper, Timothy K.; Myers, Loretha; Klein, Erin C.; Liu, Guosheng; Calvi, Carla; Podowski, Megan; Neptune, Enid R.; Halushka, Marc K.; Bedja, Djahida; Gabrielson, Kathleen; Rifkin, Daniel B.; Carta, Luca; Ramirez, Francesco; Huso, David L.; Dietz, Harry C.

In: Science, Vol. 312, No. 5770, 07.04.2006, p. 117-121.

Research output: Contribution to journalArticle

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AU - Habashi, Jennifer P.

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AU - Holm, Tammy M.

AU - Cohn, Ronald D.

AU - Loeys, Bart L.

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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Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7;312(5770):117-121. https://doi.org/10.1126/science.1124287