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J. Biol. Chem., Vol. 282, Issue 9, 6324-6337, March 2, 2007

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Prevention of Peroxynitrite-induced Apoptosis of Motor Neurons and PC12 Cells by Tyrosine-containing Peptides^*

Yaozu Ye, Celia Quijano¹, Kristine M. Robinson^¶, Karina C. Ricart^||, Amy L. Strayer^**, Mary Anne Sahawneh^**, John J. Shacka^||, Marion Kirk, Stephen Barnes, Mary Ann Accavitti-Loper, Rafael Radi², Joseph S. Beckman^¶, and Alvaro G. Estévez^**3

From the Burke Medical Research Institute, White Plains, New York 10605, Departmento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, 11800 Uruguay, ^¶Linus Pauling Institute and Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331, the ^||Department of Pathology and the Department of Pharmacology and Toxicology and Mass Spectrometry Core Facility, Comprehensive Cancer Center, and the Department of Medical Genetics and Translational Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, and the ^**Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, New York 10021

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.

Received for publication, November 21, 2006

^* This work was supported in part by NINDS Grants NS36761 (to A. G. E.), ES00040 and AT02034 (to J. S. B.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Materials and Methods" and Figs. 1–7.

¹ Supported in part by a fellowship from Programa de Desarrollo de Ciencias Básicas (PEDECIBA, Uruguay) and Fondo Cemente Estable.

² Howard Hughes International Research Scholar.

³ To whom correspondence should be addressed: Burke Medical Research Institute, White Plains, NY 10605. Tel.: 914-368-3141; Fax: 914-597-2225; E-mail: age2002{at}med.cornell.edu.

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