Intermittent hypoxia augments acute hypoxic sensing via HIF-mediated ROS.
Carotid bodies and neonatal adrenal medullary chromaffin cells (AMC) respond rapidly to acute hypoxia before compromising cellular functions. Responses to acute hypoxia are dynamically altered by chronic perturbations in arterial blood O2 levels resulting from breathing disorders. Sleep disordered breathing with recurrent apneas cause periodic decreases in arterial blood O2 or intermittent hypoxia (IH). Recent studies suggest that reactive oxygen species (ROS) mediate cellular adaptations to prolonged hypoxia. In this article we discuss the evidence for ROS in mediating exaggerated carotid body and AMC responses to acute hypoxia by IH and the underlying cellular and molecular mechanisms. IH increases ROS levels, and anti-oxidants prevent IH-induced augmented responses of the carotid body and AMC to hypoxia. The enhanced hypoxic sensitivity by IH involves ROS-dependent recruitment of transmitters/modulators in the carotid body and Ca2+ signaling mechanisms in AMC. Mechanisms by which IH elevates ROS include activation of NADPH oxidases, inhibition of mitochondrial complex I activity and down-regulation of anti-oxidant enzymes. Transcriptional regulation of pro- and anti-oxidant enzymes by hypoxia-inducible factors 1 and 2 appears to be a major molecular mechanism regulating ROS generation by IH.
Prabhakar
Nanduri R
NR
Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, IL 60637, USA. nanduri@uchicago.edu
Kumar
Ganesh K
GK
Nanduri
Jayasri
J
D000818:Animals; D002344:Carotid Body / Q000166:cytology; D019439:Chromaffin Cells / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D010100:Oxygen
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