Histochemistry and Cell Biology

, Volume 126, Issue 3, pp 335–342 | Cite as

Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology

  • Ilpo Koskivirta
  • Otto Rahkonen
  • Mikko Mäyränpää
  • Sari Pakkanen
  • Michael Husheem
  • Annele Sainio
  • Harri Hakovirta
  • Jukka Laine
  • Eero Jokinen
  • Eero Vuorio
  • Petri Kovanen
  • Hannu Järveläinen
Original paper

Abstract

Tissue inhibitors of matrix metalloproteinases (TIMPs) comprise a family of four members, of which TIMP4 is characterized by being primarily restricted to cardiovascular structures. We demonstrate with immunohistochemical analysis of healthy human tissue that TIMP4 is present in medial smooth muscle cells and adventitial capillaries of arteries as well as in cardiomyocytes. Animal studies have suggested a role for TIMP4 in several inflammatory diseases and cardiovascular pathologies. We therefore examined whether TIMP4 is involved in human inflammatory cardiovascular disorders, specifically atherosclerosis, giant cell arteritis and chronic rejection of heart allografts. TIMP4 was most clearly visible in cardiovascular tissue areas populated by abundant inflammatory cells, mainly macrophages and CD3+ T cells. Using western blotting and immunocytochemistry, human blood derived lymphocytes, monocytes/macrophages and mast cells were shown to produce TIMP4. In advanced atherosclerotic lesions, TIMP4 was detected around necrotic lipid cores, whereas TIMP3 and caspase 3 resided within and around the core regions, indicating different roles for TIMP3 and TIMP4 in inflammation-induced apoptosis and in matrix turnover. In conclusion, the data demonstrate upregulation of TIMP4 in human cardiovascular disorders exhibiting inflammation, suggesting its future use as a novel systemic marker for vascular inflammation.

Keywords

TIMP4 Inflammation Atherosclerosis Giant cell arteritis Heart allograft rejection 

Notes

Acknowledgements

The authors thank Tuula Oivanen for expert technical assistance. David Smookler is acknowledged for reviewing the language of this study. Ilpo Koskivirta is a recipient of the fellowship from the Turku Graduate School of Biomedical Sciences. This study has been supported by Finnish Medical Foundation (Ilpo Koskivirta, Otto Rahkonen), scholarships of University of Turku (Ilpo Koskivirta), Finnish Foundation for Cardiovascular Research (Hannu Järveläinen) and Medical Research Fund (EVO) of Turku University Central Hospital (Hannu Järveläinen).

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ilpo Koskivirta
    • 1
    • 5
  • Otto Rahkonen
    • 1
    • 6
  • Mikko Mäyränpää
    • 7
  • Sari Pakkanen
    • 1
  • Michael Husheem
    • 2
  • Annele Sainio
    • 1
  • Harri Hakovirta
    • 3
  • Jukka Laine
    • 4
  • Eero Jokinen
    • 6
  • Eero Vuorio
    • 1
  • Petri Kovanen
    • 7
  • Hannu Järveläinen
    • 1
    • 5
  1. 1.Department of Medical Biochemistry and Molecular BiologyUniversity of TurkuTurkuFinland
  2. 2.Department of Anatomy University of TurkuTurkuFinland
  3. 3.Department of Surgery University of TurkuTurkuFinland
  4. 4.Department of PathologyUniversity of TurkuTurkuFinland
  5. 5.Department of Medicine, Turku University Central HospitalUniversity of TurkuTurkuFinland
  6. 6.Department of PediatricsUniversity of HelsinkiHelsinkiFinland
  7. 7.Wihuri Research InstituteHelsinkiFinland

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