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

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.

Mice with Tissue Inhibitor of Metalloproteinases 4 (Timp4) Deletion Succumb to Induced Myocardial Infarction but Not to Cardiac Pressure Overload

“…High expression of Timp4 mRNA in the heart (9, 10), animal models of heart disease (14,15,18), and in patients with cardiovascular pathology (11,19) together suggest a specific role for TIMP4 in the development, physiology, and pathology of the cardiovascular system. Mice with a targeted deletion of Timp4 exhibited normal development, we were able to observe a cardiac phenotype only in 20-month-old Timp4 knock-out mice.…”

Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

“…The specificity of the antibodies has been tested. [13][14][15][16][17] Evaluation of all TMA stainings was done with a Zeiss light microscope at 103 objective magnification and 103 ocular magnification. The one who made these evaluations (MH) was unaware of tumor grade, stage or clinical outcome.…”

Diabetes mellitus and apoptosis: inflammatory cells

“…In addition, these data highlight the complexity of atheropathogenesis, with the likelihood that a multiple hit hypothesis rather than a single event is important in terms of disease progression. Balancing pro-apototic factors are a series of inhibitors of this process which include: Bcl-2 [107], macrophage colony-stimulating factor (M-CSF) [108], tissue inhibitors of metalloproteinases (TIMPs) [109], survivin [108], TOSO [110], FLICE-like inhibitory protein (FLIP) [111], Bfl-1, and Mcl-1 [112]. The importance of considering the temporal aspects of macrophage apoptosis in atherosclerosis is illustrated by recent work on survivin, a caspase inhibitor of the inhibitors of apoptosis (IAP) family, which is transcribed specifically during mitosis and is usually absent in normal adult tissues.…”