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-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.affiliation: Howard Hughes Medical Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Habashi
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Holm
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Cohn
authors.forename: Bart L
authors.initials: BL
authors.lastname: Loeys
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Loretha
authors.initials: L
authors.lastname: Myers
authors.forename: Erin C
authors.initials: EC
authors.lastname: Klein
authors.forename: Guosheng
authors.initials: G
authors.lastname: Liu
authors.forename: Carla
authors.initials: C
authors.lastname: Calvi
authors.forename: Megan
authors.initials: M
authors.lastname: Podowski
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Kathleen
authors.initials: K
authors.lastname: Gabrielson
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.forename: Luca
authors.initials: L
authors.lastname: Carta
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000473:pathology; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy / Q000473:pathology; D008382:Marfan Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D009154:Mutation; D009500:Neutralization Tests; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy; D011433:Propranolol / Q000008:administration & dosage / Q000627:therapeutic use; D011650:Pulmonary Alveoli / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D054392:Adipokines
chemical_list: D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000906:Antibodies; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan; D008840:Microfilament Proteins; D011433:Propranolol; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines