| First Author | Guo G | Year | 2013 |
| Journal | Hum Mol Genet | Volume | 22 |
| Issue | 3 | Pages | 433-43 |
| PubMed ID | 23100322 | Mgi Jnum | J:191125 |
| Mgi Id | MGI:5461085 | Doi | 10.1093/hmg/dds439 |
| Citation | Guo G, et al. (2013) Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice. Hum Mol Genet 22(3):433-43 |
| abstractText | Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fi brillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-beta) 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 signi fi cantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage in fi 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 fi ndings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced in fl 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. |
