Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.
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.
Habashi
Jennifer P
JP
Howard Hughes Medical Institute and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Judge
Daniel P
DP
Holm
Tammy M
TM
Cohn
Ronald D
RD
Loeys
Bart L
BL
Cooper
Timothy K
TK
Myers
Loretha
L
Klein
Erin C
EC
Liu
Guosheng
G
Calvi
Carla
C
Podowski
Megan
M
Neptune
Enid R
ER
Halushka
Marc K
MK
Bedja
Djahida
D
Gabrielson
Kathleen
K
Rifkin
Daniel B
DB
Carta
Luca
L
Ramirez
Francesco
F
Huso
David L
DL
Dietz
Harry C
HC
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
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