title: Expression of membrane-type 1 matrix metalloproteinase in coronary vessels of allotransplanted primate hearts.
abstract: BACKGROUND
  The mechanisms of intimal thickening in cardiac allograft vasculopathy (CAV) remain controversial after heart transplantation. Matrix metalloproteinase-2 (MMP-2) plays a crucial role in degrading extracellular matrix (ECM) during neointimal formation. Recently, it has been revealed that MMP-2 is activated by membrane-type 1 matrix metalloproteinase (MT1-MMP). This process involves tissue inhibitor of MMP-2 (TIMP-2), forming an MT1-MMP/TIMP-2/pro-MMP-2 complex. In this study, we hypothesize that these components contribute to the pathogenesis of CAV.
  
  
  METHODS
  Heterotopic cardiac allografting was performed in randomly paired Japanese monkeys with an immunosuppressive regimen of intravenous administration of antihuman CD18 monoclonal antibody. The donor hearts were harvested at Days 22, 28, 40, 41, and 95 posttransplantation. We examined expression of MMP-2, MT1-MMP, and TIMP-2 of graft vessels using immunohistochemistry and protein level by western blot analysis.
  
  
  RESULTS
  Pathologically, various degrees of neointimal formation were observed. In the allografts harvested at Days 22, 28, 40, and 41, MT1-MMP was expressed in the endothelial cells and smooth muscle cells (SMCs) in media of some arteries without histological change, accompanied by expression of MMP-2 and TIMP-2. In the severely thickened neointima of the allograft harvested at Day 95, MMP-2 and faint MT1-MMP were expressed in SMCs of severely thickened neointima and media; TIMP-2 expression was seen only in noncollagenous tissue of severely thickened neointima. MMP-2 protein was more intensely expressed in the allograft harvested at Day 95 than in the allograft harvest at Day 41, while TIMP-2 protein level was almost same in the 2 samples.
  
  
  CONCLUSIONS
  We observed the simultaneous expression of MMP-2, MT1-MMP, and TIMP-2. Thus, ECM degradation triggered by MT1-MMP/TIMP-2/pro-MMP-2 complex could be a novel mechanism of CAV.
authors: Second Department of Surgery, Shinshu University, School of Medicine, Nagano, Japan.
authors: K
authors: K
authors: Tsukioka
authors: J
authors: J
authors: Suzuki
authors: M
authors: M
authors: Kawauchi
authors: Y
authors: Y
authors: Wada
authors: T
authors: T
authors: Zhang
authors: A
authors: A
authors: Nishio
authors: N
authors: N
authors: Koide
authors: M
authors: M
authors: Endoh
authors: K
authors: K
authors: Takayama
authors: S
authors: S
authors: Takamoto
authors: M
authors: M
authors: Isobe
authors: J
authors: J
authors: Amano
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D015153:Blotting, Western; D018821:CD18 Antigens / Q000276:immunology; D003327:Coronary Disease / Q000201:enzymology / Q000209:etiology; D003331:Coronary Vessels / Q000201:enzymology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007275:Injections, Intravenous; D008251:Macaca; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D011897:Random Allocation; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology; D017540:Tunica Media / Q000201:enzymology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D004792:Enzyme Precursors; D007166:Immunosuppressive Agents; D019716:Tissue Inhibitor of Metalloproteinase-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2