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Reactive oxygen radicals and gaseous transmitters in carotid body activation by intermittent hypoxia

Abstract

Sleep apnea is a prevalent respiratory disease characterized by periodic cessation of breathing during sleep causing intermittent hypoxia (IH). Sleep apnea patients and rodents exposed to IH exhibit elevated sympathetic nerve activity and hypertension. A heightened carotid body (CB) chemoreflex has been implicated in causing autonomic abnormalities in IH-treated rodents and in sleep apnea patients. The purpose of this article is to review the emerging evidence showing that interactions between reactive oxygen species (ROS) and gaseous transmitters as a mechanism cause hyperactive CB by IH. Rodents treated with IH exhibit markedly elevated ROS in the CB, which is due to transcriptional upregulation of pro-oxidant enzymes by hypoxia-inducible factor (HIF)-1 and insufficient transcriptional regulation of anti-oxidant enzymes by HIF-2. ROS, in turn, increases cystathionine γ-lyase (CSE)-dependent H2S production in the CB. Blockade of H2S synthesis prevents IH-evoked CB activation. However, the effects of ROS on H2S production are not due to direct effects on CSE enzyme activity but rather due to inactivation of heme oxygenase-2 (HO-2), a carbon monoxide (CO) producing enzyme. CO inhibits H2S production through inactivation of CSE by PKG-dependent phosphorylation. During IH, reduced CO production resulting from inactivation of HO-2 by ROS releases the inhibition of CO on CSE thereby increasing H2S. Inhibiting H2S synthesis prevented IH-evoked sympathetic activation and hypertension.

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Fig. 1

Abbreviations

CB:

Carotid body

IH:

Intermittent hypoxia

OSA:

Obstructive sleep apnea

CSE:

Central sleep apnea

ROS:

Reactive oxygen species

CSE:

Cystathionine γ-lyase

CBS:

Cystathionine β-synthase

HO-2:

Heme oxgenase-2

CO:

Carbon monoxide

H2S:

Hydrogen sulfide

H2O2 :

Hydrogen peroxide

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Acknowledgements

This work was supported by National Institutes of Health grants P01-HL-90554 and UH2-HL-123610.

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Correspondence to Nanduri R. Prabhakar.

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The authors declare that they have no conflict of interest.

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Prabhakar, N.R., Peng, Y., Yuan, G. et al. Reactive oxygen radicals and gaseous transmitters in carotid body activation by intermittent hypoxia. Cell Tissue Res 372, 427–431 (2018). https://doi.org/10.1007/s00441-018-2807-0

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Keywords

  • Sleep apnea
  • Carbon monoxide
  • Hydrogen sulfide
  • Heme oxygenase-2
  • Cystathionine γ-lyase