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B activation in hydrogen peroxide-treated human endothelial cells
1 Division of Life Sciences and Silver Biotechnology Research Center, Hallym University, Chuncheon, Kangwon-do, Korea, Republic of
2 Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
* To whom correspondence should be addressed. E-mail: yhkang{at}hallym.ac.kr.
We recently reported that pyruvate inhibited translocation and activation of p53 caused by DNA damage due to oxidant injury; this was associated with increased expression of apoptosis-related bcl-2 at decreased expression of bax gene. This study attempted to delineate possible regulatory sites and mechanisms of anti-apoptotic pyruvate, focusing on reactive oxygen species (ROS)-mediated signaling in a human umbilical vein endothelial cell model. Effects of cytosolic reductant L-lactate and malate-aspartate shuttle blocker aminooxyacetate, both of which increase cytosolic NADH, on the signaling pathway downstream were measured for comparisons. Hydrogen peroxide (0.5 mM H2O2) depleted intracellular total glutathione that was prevented by pyruvate but not 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 or aminooxyacetate, implicating redox-related anti-apoptotic mechanisms of pyruvate. Western blot analysis and immunochemical data revealed that also H2O2-induced transactivation of nuclear factor-
B (NF-B) was inhibited by pyruvate, but not L-lactate or aminooxyacetate. In addition, H2O2 down-regulated extracellular signal-regulated kinase (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (p38 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 the enhanced antioxidant potential desensitized nuclear NF-B transactivation due to ROS, suggesting possible metabolic redox relations to NF-B. Furthermore, pyruvate blocked p38 MAPK pathway and activated ERK pathway in a redox-sensitive manner, which may regulate expression of genes that are believed to prevent apoptosis and promote cell survival. Thus, pyruvate may have therapeutic potential for reducing endothelial dysfunction and improving survival during oxidative stress.
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