title: Indomethacin Prevents the Progression of Thoracic Aortic Aneurysm in Marfan Syndrome Mice.
abstract: BACKGROUND
  Marfan syndrome (MFS), an inherited disorder of connective tissue characterized by abnormalities in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The high mortality in untreated patients is primarily due to aneurysm and dissection of the ascending aorta. The complex pathogenesis of MFS involves changes in transforming growth factor β (TGF-β) signaling, increased matrix metalloproteinase (MMP) expression, and fragmentation of the extracellular matrix. A number of studies have demonstrated increased counts of macrophages and T cells in the ascending aorta of persons or mouse models of MFS, but the efficacy of anti-inflammatory therapy in mouse models of MFS has not yet been assessed.
  
  
  METHODS
  FBN1 underexpressing mgR/mgR Marfan mice were treated with oral indomethacin. Treatment was begun at the age of three weeks and continued for 8 weeks, following which the aorta of wild type as well as treated and untreated mgR/mgR mice was compared.
  
  
  RESULTS
  Indomethacin treatment led to a statistically significant reduction of aortic elastin degeneration and macrophage infiltration, as well as a lessening of MMP-2, MMP-9, and MMP-12 upregulation. Additionally, indomethacin decreased both cyclooxygenases 2 (COX-2) expression and activity in the aorta of mgR/mgR mice. COX-2-mediated inflammatory infiltrate contributes to the progression of aortic aneurysm in mgR/mgR mice, providing evidence that COX-2 is a relevant therapeutic target in MFS-associated aortic aneurysmal disease.
  
  
  CONCLUSIONS
  COX-2 mediated inflammatory infiltration plays an important role in the pathogenesis of aortic aneurysm disease in MFS.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Gao
authors.initials: G
authors.lastname: Guo
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Claus-Eric
authors.initials: CE
authors.lastname: Ott
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Grünhagen
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Begoña
authors.initials: B
authors.lastname: Muñoz-García
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
authors.forename: Angelika
authors.initials: A
authors.lastname: Pletschacher
authors.affiliation: Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Kallenbach
authors.affiliation: Centre of Cardiology and Cardiovascular Surgery, Department of Cardiology/Angiology, University Hospital, Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Yskert
authors.initials: Y
authors.lastname: von Kodolitsch
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany; ; Max-Planck-Institute for Molecular Genetics, Berlin, Germany; ; Berlin Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
keywords: Aneurysm; Aorta; Inflammatory infiltrate; Marfan syndrome