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HIGHLIGHTED TOPICS
Oxygen Sensing in Health and Disease

Enhanced survival effect of pyruvate correlates MAPK and NF-B activation in hydrogen peroxide-treated human endothelial cells

¹Division of Life Sciences and Silver Biotechnology Research Center, Hallym University, Chuncheon 200-702, Korea; and ²Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

Submitted 29 July 2003 ; accepted in final form 8 October 2003

We recently reported that pyruvate inhibited translocation and activation of p53 caused by DNA damage due to oxidant injury (Lee YJ, Kang IJ, Bünger R, and Kang YH. Microvasc Res 66: 91-101, 2003); this was associated with increased expression of apoptosis-related bcl-2 and decreased expression of bax gene. This study attempted to delineate possible regulatory sites and mechanisms of antiapoptotic pyruvate, focusing on reactive oxygen species-mediated signaling in a human umbilical vein endothelial cell model. We compared the effects of the cytosolic reductant L-lactate and malate-aspartate shuttle blocker aminooxyacetate, both of which increase cytosolic NADH, on the downstream signaling pathway. Hydrogen peroxide (0.5 mM H₂O₂) depleted intracellular total glutathione that was prevented by pyruvate but not by L-lactate or aminooxyacetate. Activation of caspase-3 and the cleavage of procaspase-6 and procaspase-7 were strongly inhibited by pyruvate but markedly enhanced by L-lactate and aminooxyacetate, implicating redox-related antiapoptotic mechanisms of pyruvate. Western blot analysis and immunochemical data revealed that H₂O₂-induced transactivation of nuclear factor-B (NF-B) was also inhibited by pyruvate but not by L-lactate or aminooxyacetate. In addition, H₂O₂ downregulated extracellular signal-regulated kinase (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (MAPK), effects that were fully reversed by pyruvate within 2 h. Collectively, these findings indicate that pyruvate can protect cellular glutathione, thus enhancing cellular antioxidant potential, and that enhanced antioxidant potential can desensitize NF-B transactivation due to reactive oxygen species, suggesting possible metabolic redox relations to NF-B. Furthermore, pyruvate blocked the p38 MAPK pathway and activated the ERK pathway in an apparently redox-sensitive manner, which may regulate expression of genes believed to prevent apoptosis and promote cell survival. Thus pyruvate may have therapeutic potential for reducing endothelial dysfunction and improving survival during oxidative stress.

apoptosis; caspase-3; reactive oxygen species

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