Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology
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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.
KeywordsTIMP4 Inflammation Atherosclerosis Giant cell arteritis Heart allograft rejection
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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