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Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice.
Guo, Gao; Muñoz-García, Begoña; Ott, Claus-Eric; Grünhagen, Johannes; Mousa, Shaaban A; Pletschacher, Angelika; von Kodolitsch, Yskert; Knaus, Petra; Robinson, Peter N.
Afiliação
  • Guo G; Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
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 fibrillin-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 significantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage infiltration 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 findings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced inflammatory 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.
Assuntos

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

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