title: Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory cytokines.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) are thought to play a prominent role in atherogenesis and destabilization of plaque. Pericellularly localized membrane-type (MT)-MMPs activate secreted MMPs. We investigated the hypothesis that MT3-MMP is expressed in human atherosclerotic plaques and is regulated by locally produced inflammatory cytokines and oxidized low-density lipoprotein (Ox-LDL).
  
  
  RESULTS
  Expression and cellular localization of MT3-MMP in normal and atherosclerotic human coronary arteries were examined using specific antibodies. Abundant MT3-MMP expression was noted in medial smooth muscle cells (SMCs) of normal arteries. In atherosclerotic arteries, MT3-MMP expression was observed within complex plaques and colocalized with SMCs and macrophages (Mphi). Cultured human monocyte-derived Mphi constitutively expressed MT3-MMP mRNA and proteolytically active protein, as demonstrated by mRNA analyses, immunoblotting, and gelatin zymography, respectively. Ox-LDL, tumor necrosis factor-alpha, or macrophage colony-stimulating factor caused dose- and time-dependent increases in steady-state levels of MT3-MMP mRNA in cultured Mphi. This correlated with a 2- to 4-fold increase in levels of MT3-MMP immunoreactive protein and enzymatic activity in Mphi membranes. Confocal microscopy and flow cytometry confirmed induction and spatial distribution of MT3-MMP protein from intracellular domains to the Mphi plasma membrane by Ox-LDL, tumor necrosis factor-alpha, or macrophage colony-stimulating factor.
  
  
  CONCLUSIONS
  MT3-MMP is expressed by SMCs and Mphi in human atherosclerotic plaques. Proinflammatory molecules cause a progressive increase in the expression of MT3-MMP in cultured Mphi. Our results suggest a mechanism by which inflammatory molecules could promote Mphi-mediated degradation of extracellular matrix and thereby contribute to plaque destabilization.
authors.affiliation: Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif 90048-1865, USA.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Uzui
authors.forename: Alice
authors.initials: A
authors.lastname: Harpf
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Terence M
authors.initials: TM
authors.lastname: Doherty
authors.forename: Arun
authors.initials: A
authors.lastname: Shukla
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Chai
authors.forename: Pinky V
authors.initials: PV
authors.lastname: Tripathi
authors.forename: Stefan
authors.initials: S
authors.lastname: Jovinge
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Wilkin
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Asotra
authors.forename: Prediman K
authors.initials: PK
authors.lastname: Shah
authors.forename: Tripathi B
authors.initials: TB
authors.lastname: Rajavashisth
mesh_terms: D001161:Arteriosclerosis / Q000201:enzymology* / Q000473:pathology*; D015152:Blotting, Northern; D002384:Catalysis; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D016173:Macrophage Colony-Stimulating Factor; D019278:Matrix Metalloproteinase 3