Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4

Peroxynitrite, via post-translational modifications to target proteins, contributes to cardiovascular injury and cancer. Since tissue inhibitor of metalloproteinase-4 (TIMP-4), the activity of which is impaired in both pathological conditions, has several amino acid residues susceptible to peroxynit...

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Bibliographic Details
Published in:FEBS letters 2008-04, Vol.582 (7), p.1135-1140
Main Authors: Donnini, Sandra, Monti, Martina, Roncone, Raffaella, Morbidelli, Lucia, Rocchigiani, Marina, Oliviero, Salvatore, Casella, Luigi, Giachetti, Antonio, Schulz, Richard, Ziche, Marina
Format: Article
Language:English
Subjects:
Animals
Cattle
Cell invasiveness
Cell Line, Tumor
Cell Movement
Cells, Cultured
Endothelium, Vascular - cytology
Humans
Metalloproteinase-2
Nitrative stress
Peroxynitrite
Peroxynitrous Acid - pharmacology
Tissue Inhibitor of Metalloproteinase-4
Tissue Inhibitor of Metalloproteinases - antagonists & inhibitors
Tissue Inhibitor of Metalloproteinases - chemistry
Tissue Inhibitor of Metalloproteinases - metabolism
Tyrosine - analogs & derivatives
Tyrosine - analysis
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Summary:Peroxynitrite, via post-translational modifications to target proteins, contributes to cardiovascular injury and cancer. Since tissue inhibitor of metalloproteinase-4 (TIMP-4), the activity of which is impaired in both pathological conditions, has several amino acid residues susceptible to peroxynitrite, we investigated its role as a potential target of peroxynitrite. Peroxynitrite-induced nitration and oligomerization of TIMP-4 attenuated its inhibitory activity against MMP-2 activity and endothelial or tumor cell invasiveness. Moreover, cell treatment with peroxynitrite promoted the nitration of endogenous TIMP-4. HPLC/ESI-MS/MS analysis of peroxynitrite-treated TIMP-4 showed modifications at Y114, Y195, Y188 and Y190. In conclusion, TIMP-4 nitration might be a potential mechanism contributing to cardiovascular disease and cancer.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2008.02.080