title: Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata.
abstract: OBJECTIVE
  Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown.
  
  
  RESULTS
  We detected enhanced FAP expression in type IV-V human aortic atheromata (n = 12), compared with type II-III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 µm) vs. thick-cap (≥ 65 µm) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R(2)= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor α (TNFα) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFα (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01).
  
  
  CONCLUSIONS
  Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFα. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous caps.
authors.affiliation: Cardiovascular Research,  Institute of Physiology, Zurich University, Winterthurerstrasse 190, CH-8057 Zurich,  Switzerland.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Brokopp
authors.forename: Roman
authors.initials: R
authors.lastname: Schoenauer
authors.forename: Peter
authors.initials: P
authors.lastname: Richards
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Christine
authors.initials: C
authors.lastname: Lohmann
authors.forename: Maximilian Y
authors.initials: MY
authors.lastname: Emmert
authors.forename: Benedikt
authors.initials: B
authors.lastname: Weber
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Kirk
authors.initials: K
authors.lastname: Graves
authors.forename: Michele
authors.initials: M
authors.lastname: Genoni
authors.forename: Peter
authors.initials: P
authors.lastname: Vogt
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hoerstrup
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001018:Aortic Diseases / Q000378:metabolism*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D017364:Collagenases; D003324:Coronary Artery Disease / Q000378:metabolism*; D010450:Endopeptidases; D042783:Endothelial Cells / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D024042:Collagen Type I; D017364:Collagenases; D010450:Endopeptidases; D018093:Gelatinases; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D014409:Tumor Necrosis Factor-alpha; D000099167:Fibroblast Activation Protein Alpha; C417249:collagenase 1