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J. Biol. Chem., Vol. 282, Issue 21, 15506-15515, May 25, 2007

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Vitamin C Is an Essential Antioxidant That Enhances Survival of Oxidatively Stressed Human Vascular Endothelial Cells in the Presence of a Vast Molar Excess of Glutathione^*

Viviana Montecinos¹², Paula Guzmán¹², Valeria Barra, Marcelo Villagrán, Carola Muñoz-Montesino³, Kirsty Sotomayor¹, Elizabeth Escobar¹, Alejandro Godoy¹, Lorena Mardones, Paula Sotomayor, Catherine Guzmán¹, Osmán Vásquez, Victoria Gallardo, Brigitte van Zundert, María Rosa Bono, Sergio A. Oñate^¶, Marcelo Bustamante^||, Juan G. Cárcamo^**, Coralia I. Rivas, and Juan Carlos Vera⁴

From the Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160C, Concepción, Chile, the Departamento de Bioquímica, Facultad de Ciencias, Universidad de Chile, Casilla 297, Santiago, Chile, the ^¶Roswell Park Cancer Institute, Buffalo, New York 14263, the ^||Facultad de Medicina, Universidad Católica de la Santísima Concepción, Casilla 653, Concepción, Chile, and the ^**Instituto de Bioquímica, Facultad de Ciencias, Universidad Austral de Chile, Casilla 567, Valdivia, Chile

Cellular glutathione levels may exceed vitamin C levels by 10-fold, generating the question about the real antioxidant role that low intracellular concentrations of vitamin C can play in the presence of a vast molar excess of glutathione. We characterized the metabolism of vitamin C and its relationship with glutathione in primary cultures of human endothelial cells oxidatively challenged by treatment with hydrogen peroxide or with activated cells undergoing the respiratory burst, and analyzed the manner in which vitamin C interacts with glutathione to increase the antioxidant capacity of cells. Our data indicate that: (i) endothelial cells express transporters for reduced and oxidized vitamin C and accumulate ascorbic acid with participation of glutathione-dependent dehydroascorbic acid reductases, (ii) although increased intracellular levels of vitamin C or glutathione caused augmented resistance to oxidative stress, 10-times more glutathione than vitamin C was required, (iii) full antioxidant protection required the simultaneous presence of intracellular and extracellular vitamin C at concentrations normally found in vivo, and (iv) intracellular vitamin C cooperated in enhancing glutathione recovery after oxidative challenge thus providing cells with enhanced survival potential, while extracellular vitamin C was recycled through a mechanism involving the simultaneous neutralization of oxidant species. Therefore, in endothelial cells under oxidative challenge, vitamin C functions as an essential cellular antioxidant even in the presence of a vast molar excess of glutathione.

Received for publication, August 31, 2006 , and in revised form, March 28, 2007.

^* This work was supported in part by Grant Anillo de Ciencia y Tecnología ACT28 from Proyecto Bicentenario, Grants 1020451 and 1040475 from Fondecyt, and Grant DIUC 03.C4.01 from the Dirección de Investigación, Universidad de Concepción. This work was also supported in part by Grant UCH0115 from Mecesup for student travel fellowships and equipment. 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.

¹ Supported by predoctoral fellowships from Conicyt.

² These authors made equal contributions to this work.

³ Supported by predoctoral fellowships from Mecesup and the University of Concepción.

⁴ To whom correspondence should be addressed: Dept. de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, Barrio Universitario S/N, Concepción, Casilla 160C, Chile. Tel.: 56-41-2203817; Fax: 56-41-2216558; E-mail: juvera{at}udec.cl.

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