title: Matricellular proteins and matrix metalloproteinases mark the inflammatory and fibrotic response in human cardiac allograft rejection.
abstract: OBJECTIVE
  The cardiac extracellular matrix is highly involved in regulating inflammation, remodelling, and function of the heart. Whether matrix alterations relate to the degree of inflammation, fibrosis, and overall rejection in the human transplanted heart remained, until now, unknown.
  
  
  RESULTS
  Expression of matricellular proteins, proteoglycans, and metalloproteinases (MMPs) and their inhibitors (TIMPs) were investigated in serial endomyocardial biopsies (n = 102), in a cohort of 39 patients within the first year after cardiac transplantation. Out of 15 matrix-related proteins, intragraft transcript and protein levels of syndecan-1 and MMP-9 showed a strong association with the degree of cardiac allograft rejection (CAR), the expression of pro-inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β, and with infiltrating CD3⁺ T-cells and CD68⁺ monocytes. In addition, SPARC, CTGF, TSP-2, MMP-14, TIMP-1, Testican-1, TSP-1, Syndecan-1, MMP-2, -9, and -14, as well as IL-6 and TGF-β transcript levels and inflammatory infiltrates all strongly relate to collagen expression in the transplanted heart. More importantly, receiver operating characteristic curve analysis demonstrated that syndecan-1 and MMP-9 transcript levels had the highest area under the curve (0.969 and 0.981, respectively), thereby identifying both as a potential decision-making tool to discriminate rejecting from non-rejecting hearts.
  
  
  CONCLUSIONS
  Out of 15 matrix-related proteins, we identified synd-1 and MMP-9 intragraft transcript levels of as strong predictors of human CAR. In addition, a multitude of non-structural matrix-related proteins closely associate with collagen expression in the transplanted heart. Therefore, we are convinced that these findings deserve further investigation and are likely to be of clinical value to prevent human CAR.
authors.affiliation: Cardiovascular Diseases, University Hospitals Leuven, and Department of Cardiovascular Sciences, KU Leuven, Belgium. Davyvanhoutte@gmail.com
authors.forename: Davy
authors.initials: D
authors.lastname: Vanhoutte
authors.forename: Geert C
authors.initials: GC
authors.lastname: van Almen
authors.forename: Lucas N L
authors.initials: LN
authors.lastname: Van Aelst
authors.forename: Johan
authors.initials: J
authors.lastname: Van Cleemput
authors.forename: Walter
authors.initials: W
authors.lastname: Droogné
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Johan
authors.initials: J
authors.lastname: Vanhaecke
authors.forename: Anna-Pia
authors.initials: AP
authors.lastname: Papageorgiou
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
mesh_terms: D064591:Allografts; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D011509:Proteoglycans; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases
keywords: Biomarker; Cardiac matrix; Heart transplantation; Inflammation; Matricellular proteins; Metalloproteinases; Rejection