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J. Biol. Chem., Vol. 278, Issue 40, 38484-38494, October 3, 2003

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Aldose Reductase Induced by Hyperosmotic Stress Mediates Cardiomyocyte Apoptosis

DIFFERENTIAL EFFECTS OF SORBITOL AND MANNITOL^*

Anita S. Galvez  , Juan Alberto Ulloa , Mario Chiong , Alfredo Criollo , Verónica Eisner  , Luis Felipe Barros ¶ and Sergio Lavandero  || ** 

From the Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, ^||Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina y ^**Centro FONDAP Estudios Moleculares de la Célula, Universidad de Chile, Santiago 6640750, Chile, and ^¶Centro de Estudios Científicos, Casilla 1469, Valdivia, Chile

Cells adapt to hyperosmotic conditions by several mechanisms, including accumulation of sorbitol via induction of the polyol pathway. Failure to adapt to osmotic stress can result in apoptotic cell death. In the present study, we assessed the role of aldose reductase, the key enzyme of the polyol pathway, in cardiac myocyte apoptosis. Hyperosmotic stress, elicited by exposure of cultured rat cardiac myocytes to the nonpermeant solutes sorbitol and mannitol, caused identical cell shrinkage and adaptive hexose uptake stimulation. In contrast, only sorbitol induced the polyol pathway and triggered stress pathways as well as apoptosis-related signaling events. Sorbitol resulted in activation of the extracellular signal-regulated kinase (ERK), p54 c-Jun N-terminal kinase (JNK), and protein kinase B. Furthermore, sorbitol treatment resulting in induction and activation of aldose reductase, decreased expression of the antiapoptotic protein Bcl-xL, increased DNA fragmentation, and glutathione depletion. Apoptosis was attenuated by aldose reductase inhibition with zopolrestat and also by glutathione replenishment with N-acetylcysteine. In conclusion, our data show that hypertonic shrinkage of cardiac myocytes alone is not sufficient to induce cardiac myocyte apoptosis. Hyperosmolarity-induced cell death is sensitive to the nature of the osmolyte and requires induction of aldose reductase as well as a decrease in intracellular glutathione levels.

Received for publication, November 20, 2002 , and in revised form, July 15, 2003.

^* This work was supported in part by FONDECYT Grant 1010246 (to S. L.), FONDAP Grant 15010006 (to S. L.), and University of Chile Graduate Grant PG 58-2000 (to A. S. G.). The Centro de Estudios Científicos is a Millennium Science Institute. 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.

Recipient of a fellowship from CONICYT, Chile.

To whom correspondence should be addressed: Dept. de Bioquímica y Biología Molecular, Centro FONDAP Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Olivos 1007, Santiago 6640750, Chile. Tel.: 562-678-2919; Fax: 562-737-8920; E-mail: slavander{at}uchile.cl.

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