title: Peroxynitrite inactivates human-tissue inhibitor of metalloproteinase-4.
abstract: 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.
authors.affiliation: Departments of Molecular Biology, University of Siena, Via A. Moro, 2, Siena 53100, Italy. donnini4@unisi.it
authors.forename: Sandra
authors.initials: S
authors.lastname: Donnini
authors.forename: Martina
authors.initials: M
authors.lastname: Monti
authors.forename: Raffaella
authors.initials: R
authors.lastname: Roncone
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
authors.forename: Marina
authors.initials: M
authors.lastname: Rocchigiani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
authors.forename: Luigi
authors.initials: L
authors.lastname: Casella
authors.forename: Antonio
authors.initials: A
authors.lastname: Giachetti
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
mesh_terms: 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
chemical_list: D030421:Peroxynitrous Acid; D019714:Tissue Inhibitor of Metalloproteinases; D014443:Tyrosine; D000097792:Tissue Inhibitor of Metalloproteinase-4; C002744:3-nitrotyrosine