title: Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice.
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-β) 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.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
authors.forename: Gao
authors.initials: G
authors.lastname: Guo
authors.forename: Begoña
authors.initials: B
authors.lastname: Muñoz-García
authors.forename: Claus-Eric
authors.initials: CE
authors.lastname: Ott
authors.forename: Johannes
authors.initials: J
authors.lastname: Grünhagen
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Angelika
authors.initials: A
authors.lastname: Pletschacher
authors.forename: Yskert
authors.initials: Y
authors.lastname: von Kodolitsch
authors.forename: Petra
authors.initials: P
authors.lastname: Knaus
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017545:Aortic Aneurysm, Thoracic / Q000209:etiology / Q000235:genetics / Q000473:pathology; D001018:Aortic Diseases / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000071838:Fibrillin-1; D000071837:Fibrillins; D007150:Immunohistochemistry; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages; D008382:Marfan Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010455:Peptides / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D054392:Adipokines
chemical_list: D000911:Antibodies, Monoclonal; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008840:Microfilament Proteins; D010455:Peptides; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C497783:Smad2 protein, mouse; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse