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-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.

• Authors: 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
• Journal: Science (New York, N.Y.) (Science) Vol. 312 Issue 5770 Pg. 117-21 (Apr 07 2006) ISSN: 1095-9203 [Electronic] United States
• PMID: 16601194 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Angiotensin II Type 1 Receptor Blockers
• Antibodies
• Fbn1 protein, mouse
• Fibrillin-1
• Fibrillins
• Microfilament Proteins
• Receptor, Angiotensin, Type 1
• Transforming Growth Factor beta
• Propranolol
• Losartan

Topics

• Adrenergic beta-Antagonists (administration & dosage, therapeutic use)
• Angiotensin II Type 1 Receptor Blockers (administration & dosage, therapeutic use)
• Animals
• Antibodies (immunology)
• Aorta (pathology)
• Aortic Aneurysm (etiology, prevention & control)
• Disease Models, Animal
• Elastic Tissue (pathology)
• Female
• Fibrillin-1
• Fibrillins
• Losartan (administration & dosage, therapeutic use)
• Lung (pathology)
• Lung Diseases (drug therapy, pathology)
• Marfan Syndrome (complications, drug therapy, metabolism, pathology)
• Mice
• Microfilament Proteins (genetics)
• Mutation
• Neutralization Tests
• Pregnancy
• Pregnancy Complications (drug therapy)
• Propranolol (administration & dosage, therapeutic use)
• Pulmonary Alveoli (pathology)
• Receptor, Angiotensin, Type 1 (metabolism)
• Signal Transduction
• Transforming Growth Factor beta (antagonists & inhibitors, immunology, metabolism)