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 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.
Donnini
Sandra
S
Departments of Molecular Biology, University of Siena, Via A. Moro, 2, Siena 53100, Italy. donnini4@unisi.it
Monti
Martina
M
Roncone
Raffaella
R
Morbidelli
Lucia
L
Rocchigiani
Marina
M
Oliviero
Salvatore
S
Casella
Luigi
L
Giachetti
Antonio
A
Schulz
Richard
R
Ziche
Marina
M
D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D000097792:Tissue Inhibitor of Metalloproteinase-4
D030421:Peroxynitrous Acid; D019714:Tissue Inhibitor of Metalloproteinases; D014443:Tyrosine; D000097792:Tissue Inhibitor of Metalloproteinase-4; C002744:3-nitrotyrosine