title: The Extracellular Matrix Signature in Vein Graft Disease.
abstract: Vein graft disease is a major and yet unsolved problem in cardiac revascularization surgery. Although accumulation of extracellular matrix is characteristic for vein graft disease, detailed analysis of the fibrotic material is lacking. Because alterations of collagen cross-links are typical for organ fibrosis, we performed a comprehensive analysis of collagen and elastin in vein graft disease.
  
  
  
  Collagen, elastin, and their respective cross-links were analyzed using histology and amino acid analysis. The expression of collagen-modifying enzymes was analyzed using SYBR Green quantitative real-time polymerase chain reaction. Fibrillin expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction.
  
  
  
  Diseased vein grafts showed a marked increase of collagen and of intermediate collagen cross-links, which are markers for newly synthesized collagen. Furthermore, we identified in vein graft disease increased levels of mature hydroxylysine aldehyde-derived cross-links typical for skeletal tissues. This was accompanied by upregulation of lysyl hydroxylase 2 and lysyl oxidase expression. Furthermore, vein graft disease showed a reduction of the elastin/collagen ratio, using elastin cross-links as a marker of elastin content, which was accompanied by an increase of fibrillin-1.
  
  
  
  Vein graft disease was accompanied by marked alterations in the composition of the extracellular matrix. The altered collagen cross-link pattern and the reduced elastin/collagen ratio might synergistically increase the stiffness in diseased vein grafts. Furthermore, hydroxylysine aldehyde-derived cross-links can cause a decreased degradability of collagens by matrix-metalloproteinases. Our data suggest collagen cross-links as a therapeutic target in vein graft disease.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Kahle
authors.affiliation: Department of Cardiac Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmidtke
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hunzelmann
authors.affiliation: Department of Cardiac Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Bartels
authors.affiliation: Department of Cardiac Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Sievers
authors.affiliation: Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Steenbock
authors.affiliation: Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Dieter P
authors.initials: DP
authors.lastname: Reinhardt
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany; Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany. Electronic address: brinckmann@vuz.uni-luebeck.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brinckmann
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D001026:Coronary Artery Bypass; D004151:Dipeptides / Q000378:metabolism; D004549:Elastin / Q000378:metabolism*; D005260:Female; D000071838:Fibrillin-1 / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000235:genetics / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D004151:Dipeptides; D000071838:Fibrillin-1; D012333:RNA, Messenger; C007428:5,5'-dihydroxylysylnorleucine; C010991:delta-hydroxylysylnorleucine; D003094:Collagen; D004549:Elastin; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D008249:Protein-Lysine 6-Oxidase