Peroxynitrite and glutathione induced proMMP activation through S-glutathiolation via glutathione disulfide S-oxide formation, illustrating a mechanism of oxidative tissue injury.
The study identifies a unique mechanism of oxidative proMMP activation via peroxynitrite-induced protein S-glutathiolation, which may contribute to oxidative tissue injury during inflammation.
Oxidative stress may cause tissue injury through activation of the precursors of matrix metalloproteinase (proMMPs). In this study, we observed glutathione (GSH)-dependent proMMP activation induced by peroxynitrite, a potent oxidizing agent formed during inflammatory processes. Peroxynitrite strongly activated all three types of purified human proMMPs (proMMP-1, -8, and -9) in the presence of similar concentrations of GSH. Of the potential reaction products between peroxynitrite and GSH, only S-nitroglutathione (GSNO(2)) caused proMMP activation. Extensive S-glutathiolation of the proMMP protein occurred during activation of proMMP by peroxynitrite and GSH, as shown by radiolabeling studies with (35)SGSH or (3)HGSH. Evidence of appreciable S-glutathiolation persisted even after dithiothreitol and protein-denaturing treatment, however, suggesting that some S-glutathiolation did not occur through formation of simple mixed disulfide. Matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry indicated that not only peroxynitrite plus GSH but also synthetic GSNO(2) produced dithiothreitol-resistant S-glutathiolation of the synthetic peptide PRCGVPD, which is a well conserved Cys-containing sequence of the propeptide autoinhibitory domain of proMMPs. PRCGVPD S-glutathiolation is presumed to be formed through glutathione disulfide S-oxide (GS(O)SR), based on the m/z 1064. Our results illustrate a unique mechanism of oxidative proMMP activation and oxidative tissue injury during inflammation.
Okamoto et al. (Wed,) conducted a other in Oxidative stress and inflammation. Peroxynitrite and glutathione (GSH) was evaluated on proMMP activation and S-glutathiolation. Peroxynitrite and glutathione induced proMMP activation through S-glutathiolation via glutathione disulfide S-oxide formation, illustrating a mechanism of oxidative tissue injury.