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


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



Carotid body


Intermittent hypoxia


Obstructive sleep apnea


Central sleep apnea


Reactive oxygen species


Cystathionine γ-lyase


Cystathionine β-synthase


Heme oxgenase-2


Carbon monoxide


Hydrogen sulfide

H2O2 :

Hydrogen peroxide


  1. Acker T, Fandrey J, Acker H (2006) The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases. Cardiovasc Res 71:195–207

  2. Ambrosio G, Zweier JL, Duilio C, Kuppusamy P, Santoro G, Elia PP, Tritto I, Cirillo P, Condorelli M, Chiariello M (1993) Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. J Biol Chem 268:18532–18541

  3. Ayala A, Muñoz MF, Argüelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med Cell Longev 2014:360438

  4. Cistulli PA, Sullivan CE (1994) Pathophysiology of sleep apnea. In: Saunders NA, Sullivan CE (eds) Sleep and breathing. Dekker, New York, pp 405–448

  5. Del Rio R, Moya EA, Iturriaga R (2010) Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link. Eur Respir J 36:143–150

  6. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP (2010) Pathophysiology of sleep apnea. Physiol Rev 90:47–112

  7. Fitzgerald RS, Shirahata M, Chang I, Kostuk E, Kiihl S (2011) The impact of hydrogen sulfide (H(2)S) on neurotransmitter release from the cat carotid body. Respir Physiol Neurobiol 176:80–89

  8. Gardner PR (2002) Aconitase: sensitive target and measure of superoxide. Methods Enzymol 349:9–23

  9. Gardner PR, Nguyen DD, White CW (1996) Superoxide scavenging by Mn(II/III) tetrakis (1-methyl-4-pyridyl) porphyrin in mammalian cells. Arch Biochem Biophys 325:20–28

  10. Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA (2013) Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol 1:483–491

  11. Jiao Y, Li Q, Sun B, Zhang G, Rong W (2015) Hydrogen sulfide activates the carotid body chemoreceptors in cat, rabbit and rat ex vivo preparations. Respir Physiol Neurobiol 208:15–20

  12. Kim D, Kim I, Wang J, White C, Carroll JL (2015) Hydrogen sulfide and hypoxia-induced changes in TASK (K2P3/9) activity and intracellular Ca(2+) concentration in rat carotid body glomus cells. Respir Physiol Neurobiol 215:30–38

  13. Kumar P, Prabhakar NR (2012) Peripheral chemoreceptors: function and plasticity of the carotid body. Compr Physiol 2:141–219

  14. Lam SY, Liu Y, Ng KM, Lau CF, Liong EC, Tipoe GL, Fung ML (2012) Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways. Histochem Cell Biol 137:303–317

  15. Lavie P, Herer P, Hoffstein V (2000) Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 320:479–482

  16. Li Q, Sun B, Wang X, Jin Z, Zhou Y, Dong L, Jiang LH, Rong W (2010) A crucial role for hydrogen sulfide in oxygen sensing via modulating large conductance calcium-activated potassium channels. Antioxid Redox Signal 12:1179–1189

  17. Makarenko VV, Nanduri J, Raghuraman G, Fox AP, Gadalla MM, Kumar GK, Snyder SH, Prabhakar NR (2012) Endogenous H2S is required for hypoxic sensing by carotid body glomus cells. Am J Physiol Cell Physiol 303:C916–C923

  18. McCoubrey WK, Huang TJ, Maines MD (1997) Heme oxygenase-2 is a hemoprotein and binds heme through heme regulatory motifs that are not involved in heme catalysis. J Biol Chem 272:12568–12574

  19. Nanduri J, Wang N, Yuan G, Khan SA, Souvannakitti D, Peng YJ, Kumar GK, Garcia JA, Prabhakar NR (2009) Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities. Proc Natl Acad Sci U S A 106:1199–1204

  20. Nanduri J, Vaddi DR, Khan SA, Wang N, Makerenko V, Prabhakar NR (2013) Xanthine oxidase mediates hypoxia-inducible factor-2alpha degradation by intermittent hypoxia. PLoS One 8:e75838

  21. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, D'Agostino RB, Newman AB, Lebowitz MD, Pickering TG (2000) Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283:1829–1836

  22. Peng YJ, Prabhakar NR (2004) Effect of two paradigms of chronic intermittent hypoxia on carotid body sensory activity. J Appl Physiol 96:1236–1242 discussion 1196

  23. Peng YJ, Overholt JL, Kline D, Kumar GK, Prabhakar NR (2003) Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci U S A 100:10073–10078

  24. Peng YJ, Yuan G, Ramakrishnan D, Sharma SD, Bosch-Marce M, Kumar GK, Semenza GL, Prabhakar NR (2006) Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol 577:705–716

  25. Peng YJ, Nanduri J, Yuan G, Wang N, Deneris E, Pendyala S, Natarajan V, Kumar GK, Prabhakar NR (2009) NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29:4903–4910

  26. Peng Y-J, Nanduri J, Raghuraman G, Souvannakitti D, Gadalla MM, Kumar GK, Snyder SH, Prabhakar NR (2010) H2S mediates O-2 sensing in the carotid body. Proc Natl Acad Sci U S A 107:10719–10724

  27. Peng YJ, Nanduri J, Khan SA, Yuan G, Wang N, Kinsman B, Vaddi DR, Kumar GK, Garcia JA, Semenza GL, Prabhakar NR (2011) Hypoxia-inducible factor 2alpha (HIF-2alpha) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci U S A 108:3065–3070

  28. Peng YJ, Yuan G, Khan S, Nanduri J, Makarenko VV, Reddy VD, Vasavda C, Kumar GK, Semenza GL, Prabhakar NR (2014) Regulation of hypoxia-inducible factor-α isoforms and redox state by carotid body neural activity in rats. J Physiol 592:3841–3858

  29. Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378–1384

  30. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM (2013) Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177:1006–1014

  31. Prabhakar NR (2001) Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 90:1986–1994

  32. Prabhakar NR (2016) Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea. Exp Physiol 101:975–985

  33. Prabhakar NR, Semenza GL (2012) Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 92:967–1003

  34. Prabhakar NR, Dinerman JL, Agani FH, Snyder SH (1995) Carbon monoxide: a role in carotid body chemoreception. Proc Natl Acad Sci U S A 92:1994–1997

  35. Prabhakar NR, Peng YJ, Kumar GK, Nanduri J (2015) Peripheral chemoreception and arterial pressure responses to intermittent hypoxia. Compr Physiol 5:561–577

  36. Yuan G, Adhikary G, McCormick AA, Holcroft JJ, Kumar GK, Prabhakar NR (2004) Role of oxidative stress in intermittent hypoxia-induced immediate early gene activation in rat PC12 cells. J Physiol 557:773–783

  37. Yuan G, Nanduri J, Khan S, Semenza GL, Prabhakar NR (2008) Induction of HIF-1alpha expression by intermittent hypoxia: involvement of NADPH oxidase, Ca2+ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol 217:674–685

  38. Yuan G, Khan SA, Luo W, Nanduri J, Semenza GL, Prabhakar NR (2011) Hypoxia-inducible factor 1 mediates increased expression of NADPH oxidase-2 in response to intermittent hypoxia. J Cell Physiol 226:2925–2933

  39. Yuan G, Vasavda C, Peng YJ, Makarenko VV, Raghuraman G, Nanduri J, Gadalla MM, Semenza GL, Kumar GK, Snyder SH, Prabhakar NR (2015) Protein kinase G-regulated production of H2S governs oxygen sensing. Sci Signal 8:ra37

  40. Yuan G, Peng YJ, Khan SA, Nanduri J, Singh A, Vasavda C, Semenza GL, Kumar GK, Snyder SH, Prabhakar NR (2016) H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea. Sci Signal 9:ra80

  41. Zhan G, Serrano F, Fenik P, Hsu R, Kong L, Pratico D, Klann E, Veasey SC (2005) NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med 172:921–929

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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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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).

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