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COMMENTARY
HIGHLIGHTED TOPICS
Oxygen Sensing in Health and Disease
B activation in hydrogen peroxide-treated human endothelial cells," Lee and colleagues (1) altered subcellular redox states in a human endothelial cell model of hydrogen peroxide oxidative stress by using exogenous pyruvate to generate cytosolic NAD+. By imposing different subcellular redox states via metabolic regulation, these investigators correlated cell physiological outcome; that is, they correlated endothelial viability and glutathione pool size with the subcellular signaling proteins extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (p38 MAPK), both of which are thought to be involved in cellular oxidative stress responses. These investigators also evaluated nuclear translocation of nuclear factor-B (NF-B), which is thought to activate transcription factor p53, essential to hydrogen peroxide-induced apoptosis. After hydrogen peroxide injury, they noted that preincubation with pyruvate transiently enhanced downregulation of ERK1/2 phosphorylation and blocked p38 MAPK. Pyruvate also inhibited hydrogen peroxide-induced translocation of NF-B, preserved cell viability, maintained the size of the total glutathione pool, and inhibited hydrogen peroxide activation of caspases. In contrast, comparative studies with L-lactate, acetate, and aminooxyacetate did not produce similar results.
Collectively, these data indicate that regulation of MAPK and NF-B translocation during oxidative stress is redox sensitive. These results also support the notion that the antiapoptotic power of pyruvate may be mainly mediated metabolically, through the cytosolic glutathione system combined with inhibition of the formation of reactive oxygen species by NAD(P)H oxidase and/or the formation of cytosolic NADPH via unique anaplerotic mitochondrial pathways. Metabolic regulation of cytosolic and mitochondrial NAD(P)H-linked redox systems can substantially influence cell signaling critical for survival, tolerance to oxidative stress, and probably normal endothelial function. Enhanced metabolic redox status also protects normal endothelial cell function and DNA stability and may impact tolerance to oxidative stress, which has been implicated in both vascular aging and arteriosclerosis. The results of this study suggest that the underlying metabolic redox status of the endothelium may be essential to promoting or preventing endothelial aging and, perhaps, cardiovascular disease. If true, novel therapeutic approaches aimed at metabolic redox regulation may prove promising, especially when targeting cytosolic NAD+ and when exploiting the unique feature of pyruvate-dependent mitochondrial anaplerosis.
In the second article featured in this issue, "Vascular oxygen sensing: detection of novel candidates by proteomics and organ culture," Thorne and colleagues (2) employed nontraditional methodologies and modern molecular techniques to explore the elusive mechanisms of oxygen sensing in vascular smooth muscle. They hypothesized that an organ culture of vascular smooth muscle yields decreased expression of proteins critical to vascular oxygen sensing. In such organ cultures of coronary arterial smooth muscle, hypoxia-induced vasorelaxation is specifically inhibited. This observation was used in combination with proteomics to isolate novel candidate proteins as potential players in the mechanisms of vascular oxygen sensing. These investigators demonstrated that in the organ culture there were changes in expression of both smooth muscle-specific and more ubiquitously expressed proteins that could serve as potential novel targets for research into the underlying mechanisms of oxygen sensing. The findings of this study are significant in that they bring to bear new avenues of exploration based on the emerging field of proteomics. Undoubtedly, such approaches will introduce novel perspectives in the search for the mechanisms of oxygen sensing and the ever-elusive oxygen sensors.
REFERENCES
B activation in hydrogen peroxide-treated human endothelial cells. J Appl Physiol 96: 793-801, 2004.
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