title: Cellular mechanisms associated with intermittent hypoxia.
abstract: Hypoxia, i.e. decreased availability of oxygen occurs under many different circumstances and can be either continuous or intermittent. Continuous hypoxia such as that experienced during periods of high altitude leads to physiological adaptations, whereas chronic IH (intermittent hypoxia) associated with sleep-disordered breathing manifested as recurrent apneas leads to morbidity. The purpose of the present chapter is to highlight recent findings on cellular responses to IH. Studies on cell culture models of IH revealed that for a given duration and intensity, IH is more potent than continuous hypoxia in evoking transcriptional activation. IH activates HIF-1 (hypoxia-inducible factor-1), the immediate early gene c-fos, activator protein-1, nuclear factor kappaB and cAMP-response-element-binding protein. Physiological studies showed that HIF-1 plays an important role in chronic IH-induced autonomic abnormalities in mice. IH affects expression of proteins associated with neuronal survival and apoptosis, as well as post-translational modifications of proteins resulting in increased biological activity. Comparisons between continuous hypoxia and IH revealed notable differences in the kinetics of protein kinase activation, type of protein kinase being activated and the downstream targets of protein kinases. IH increases ROS (reactive oxygen species) generation both in cell culture and in intact animals, and ROS-mediated signalling mechanisms contribute to cellular and systemic responses to IH. Future studies utilizing genomic and proteomic approaches may provide important clues to the mechanisms by which IH leads to morbidity as opposed to continuous hypoxia-induced adaptations. Cellular mechanisms associated with IH (other than recurrent apneas) such as repetitive, brief ascents to altitude, however, remain to be studied.
authors: Center for Systems Biology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. nanduri@uchicago.edu
authors: Jayasri
authors: J
authors: Nanduri
authors: R Prabhakar
authors: RP
authors: Nanduri
mesh_terms: D000818:Animals; D017209:Apoptosis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015533:Transcriptional Activation
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011494:Protein Kinases; D010100:Oxygen