title: Prevention of peroxynitrite-induced apoptosis of motor neurons and PC12 cells by tyrosine-containing peptides.
abstract: Although peroxynitrite stimulates apoptosis in many cell types, whether peroxynitrite acts directly as an oxidant or the induction of apoptosis is because of the radicals derived from peroxynitrite decomposition remains unknown. Before undergoing apoptosis because of trophic factor deprivation, primary motor neuron cultures become immunoreactive for nitrotyrosine. We show here using tyrosine-containing peptides that free radical processes mediated by peroxynitrite decomposition products were required for triggering apoptosis in primary motor neurons and in PC12 cells cultures. The same concentrations of tyrosine-containing peptides required to prevent the nitration and apoptosis of motor neurons induced by trophic factor deprivation and of PC12 cells induced by peroxynitrite also prevented peroxynitrite-mediated nitration of motor neurons, brain homogenates, and PC12 cells. The heat shock protein 90 chaperone was nitrated in both trophic factor-deprived motor neurons and PC12 cells incubated with peroxynitrite. Tyrosine-containing peptides did not affect the induction of PC12 cell death by hydrogen peroxide. Tyrosine-containing peptides should protect by scavenging peroxynitrite-derived radicals and not by direct reactions with peroxynitrite as they neither increase the rate of peroxynitrite decomposition nor decrease the bimolecular peroxynitrite-mediated oxidation of thiols. These results reveal an important role for free radical-mediated nitration of tyrosine residues, in apoptosis induced by endogenously produced and exogenously added peroxynitrite; moreover, tyrosine-containing peptides may offer a novel strategy to neutralize the toxic effects of peroxynitrite.
authors.affiliation: Burke Medical Research Institute, White Plains, New York 10605, USA.
authors.forename: Yaozu
authors.initials: Y
authors.lastname: Ye
authors.forename: Celia
authors.initials: C
authors.lastname: Quijano
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Robinson
authors.forename: Karina C
authors.initials: KC
authors.lastname: Ricart
authors.forename: Amy L
authors.initials: AL
authors.lastname: Strayer
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Garner
authors.forename: John J
authors.initials: JJ
authors.lastname: Shacka
authors.forename: Marion
authors.initials: M
authors.lastname: Kirk
authors.forename: Stephen
authors.initials: S
authors.lastname: Barnes
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Accavitti-Loper
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Beckman
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Estévez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D009046:Motor Neurons / Q000473:pathology*; D016716:PC12 Cells; D010455:Peptides / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D051381:Rats; D014443:Tyrosine / Q000031:analogs & derivatives
chemical_list: D016166:Free Radical Scavengers; D005609:Free Radicals; D010455:Peptides; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine