Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice.
Hum Mol Genet
; 22(3): 433-43, 2013 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-23100322
ABSTRACT
Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for ï¬brillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-ß) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP). In this work, we test the hypothesis that antagonism of GxxPG fragments can suppress disease progression in the Marfan aorta. Fibrillin-1 underexpressing mgR/mgR Marfan mice were treated with weekly intraperitoneal (i.p.) injections of an antibody directed against GxxPG fragments. The treatment was started at 3 weeks of age and continued for 8 weeks. The treatment signiï¬cantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage inï¬ltration in the aorta of the mgR/mgR mice. Additionally, airspace enlargement and increased pSmad2 activity in the lungs of mgR/mgR animals were prevented by the treatment. Our ï¬ndings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced inï¬ammatory activity in the pathogenesis of thoracic aortic aneurysm (TAA) in mgR/mgR mice. Moreover, the results of the current study suggest that antagonism of the effects of GxxPG fragments may be a fruitful therapeutic strategy in MFS.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças da Aorta
/
Peptídeos
/
Síndrome de Marfan
/
Anticorpos Monoclonais
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article