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.
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Selected disease manifestations of Marfan syndrome reflect disturbances in TGFβ signaling.
“Thus, although caused by a mutation in an ECM molecule, selected disease manifestations of Marfan syndrome reflect disturbances in TGFβ signaling (138).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [138]
Marfan syndrome is caused by mutations in the fibrillin-1 gene, leading to reduced extracellular fibrillin-rich microfibrils that normally act as a TGFβ reservoir.
“For example, Marfan syndrome, a connective tissue disorder, is caused by mutations in the gene that encodes fibrillin-1, leading to reduced levels of extracellular fibrillin-rich microfibrils, which normally act as a TGFβ reservoir.”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [138]
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- Authors
- 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.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Habashi, Jennifer P.
- Judge, Daniel P.
- Dietz, Harry C.
- ORCID
- Venue
- Science
- Published
- 2006-04-07
- Volume
- 312
- Issue
- 5770
- Pages
- 117-121
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2152350731
- Cited by
- 1,794
- References
- 30
- Citations by year
- 2026: 52 · 2025: 58 · 2024: 58 · 2023: 54 · 2022: 72 · 2021: 74 · 2020: 81 · 2019: 75 · 2018: 98 · 2017: 95 · 2016: 90 · 2015: 105 · 2014: 122 · 2013: 118 · 2012: 118
- FWCI
- 55.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K08HL067056)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic aneurysm repair treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Keywords
- losartan, Marfan syndrome, aortic aneurysm, aortic dissection, angiotensin II type 1 receptor antagonism, TGF-beta signaling, fibrillin-1, TGF-beta neutralizing antibody, alveolar septation, drug repurposing, mouse model
- MeSH terms
- Fibrillins, Fibrillin-1, Adrenergic beta-Antagonists, Animals, Antibodies, Aorta, Aortic Aneurysm, Disease Models, Animal, Elastic Tissue, Female, Lung, Lung Diseases, Marfan Syndrome, Microfilament Proteins, Mutation, Neutralization Tests, Pregnancy, Pregnancy Complications, Propranolol, Pulmonary Alveoli, Signal Transduction, Transforming Growth Factor beta, Losartan, Receptor, Angiotensin, Type 1, Angiotensin II Type 1 Receptor Blockers, Mice, Adipokines
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