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Increased expression of membrane type 3-matrix metalloproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory cytokines

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Author

  • Hiroyasu Uzui
  • Alice Harpf
  • Ming Liu
  • Terence M Doherty
  • Arun Shukla
  • Ning-Ning Chai
  • Pinky V Tripathi
  • Stefan Jovinge
  • Douglas J Wilkin
  • Kamlesh Asotra
  • Prediman K Shah
  • Tripathi B Rajavashisth
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Summary, in English

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). METHODS AND 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.

Publishing year

2002

Language

English

Pages

3024-3030

Publication/Series

Circulation

Volume

106

Issue

24

Document type

Journal article

Publisher

Lippincott Williams & Wilkins

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

ISBN/ISSN/Other

  • ISSN: 1524-4539