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Therapeutic Targeting of the Carotid Body for Treating Sleep Apnea in a Pre-clinical Mouse Model

  • Ying-Jie Peng
  • Xiuli Zhang
  • Jayasri Nanduri
  • Nanduri R. PrabhakarEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1071)

Abstract

Sleep apnea with periodic cessation of breathing during sleep is a highly prevalent respiratory disorder affecting an estimated 10% of adults. Patients with sleep apnea exhibit several co-morbidities including hypertension, stroke, disrupted sleep, and neurocognitive and metabolic complications. Emerging evidence suggests that a hyperactive carotid body (CB) chemo reflex is an important driver of apneas in sleep apnea patients. Gasotransmitters carbon monoxide (CO) and hydrogen sulfide (H2S) play important roles in oxygen sensing by the CB. We tested the hypothesis that an augmented CB chemo reflex stemming from disrupted CO-H2S signaling may lead to sleep apnea. This possibility was tested in mice deficient in hemeoxygenase-2 (HO-2), an enzyme involved in CO synthesis, which were shown to exhibit hyperactive CB activity due to high H2S levels. We found that HO-2−/− mice exhibit a high incidence of apneas during sleep compared to wild type mice. Blocking the CB hyperactivity with L-propargylglycine, an inhibitor of cystathionine-γ-lyase (CSE), which catalyzes H2S synthesis, prevented apneas in HO-2−/− mice. These findings suggest that targeting CB with inhibitors of CSE might be a novel therapeutic strategy for preventing sleep apnea.

Keywords

Hemeoxygenase-2 Carbon monoxide Cystathionine-γ-lyase Hydrogen sulfide Obstructive Central sleep apnea 

Notes

Acknowledgements

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

References

  1. Antic NA, Heeley E, Anderson CS, Luo Y, Wang J, Neal B, Grunstein R, Barbe F, Lorenzi-Filho G, Huang S, Redline S, Zhong N, McEvoy RD (2015) The sleep apnea cardio vascular endpoints (SAVE) trial: rationale, ethics, design, and progress. Sleep 38:1247–1257CrossRefGoogle Scholar
  2. Combs D, Shetty S, Parthasarathy S (2014) Advances in positive airway pressure treatment modalities for hypoventilation syndromes. Sleep Med Clin 9:315–325CrossRefGoogle Scholar
  3. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d’Ortho MP, Erdmann E, Levy P, Simonds AK, Somers VK, Zannad F, Teschler H (2015) Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med 373:1095–1105CrossRefGoogle Scholar
  4. Dempsey JA, Smith CA, Blain GM, Xie A, Gong Y, Teodorescu M (2012) Role of central/peripheral chemoreceptors and their interdependence in the pathophysiology of sleep apnea. Adv Exp Med Biol 758:343–349CrossRefGoogle Scholar
  5. Frost & Sullivan (2016) Hidden health crisis costing America billions: underdiagnosing and undertreating obstructive sleep apnea draining healthcare system. American Academy of Sleep Medicine, DarienGoogle Scholar
  6. Gilmartin GS, Daly RW, Thomas RJ (2005) Recognition and management of complex sleep-disordered breathing. Curr Opin Pulm Med 11:485–493CrossRefGoogle Scholar
  7. Harvard Medical School Division of Sleep Medicine (2010) The price of fatigue: the surprising economic costs of unmanaged sleep apnea. Harvard Medical School Division of Sleep Medicine, BostonGoogle Scholar
  8. Ip S, D’Ambrosio C, Patel K, Obadan N, Kitsios GD, Chung M, Balk EM (2012) Auto-titrating versus fixed continuous positive airway pressure for the treatment of obstructive sleep apnea: a systematic review with meta-analyses. Syst Rev 1:20CrossRefGoogle Scholar
  9. Javaheri S, Smith J, Chung E (2009) The prevalence and natural history of complex sleep apnea. J Clin Sleep Med 5:205–211PubMedPubMedCentralGoogle Scholar
  10. Javaheri S, Germany R, Greer JJ (2016) Novel therapies for the treatment of central sleep apnea. Sleep Med Clin 11:227–239CrossRefGoogle Scholar
  11. Kara T, Narkiewicz K, Somers VK (2003) Chemoreflexes–physiology and clinical implications. Acta Physiol Scand 177:377–384CrossRefGoogle Scholar
  12. Kumar P, Prabhakar NR (2012) Peripheral chemoreceptors: function and plasticity of the carotid body. Compr Physiol 2:141–219PubMedPubMedCentralGoogle Scholar
  13. Kumar NN, Velic A, Soliz J, Shi Y, Li K, Wang S, Weaver JL, Sen J, Abbott SB, Lazarenko RM, Ludwig MG, Perez-Reyes E, Mohebbi N, Bettoni C, Gassmann M, Suply T, Seuwen K, Guyenet PG, Wagner CA, Bayliss DA (2015) Regulation of breathing by CO2 requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons. Science 348:1255–1260CrossRefGoogle Scholar
  14. 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–C923CrossRefGoogle Scholar
  15. Mansukhani MP, Wang S, Somers VK (2015) Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp Physiol 100:130–135CrossRefGoogle Scholar
  16. Morgenthaler TI, Kagramanov V, Hanak V, Decker PA (2006) Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 29:1203–1209CrossRefGoogle Scholar
  17. 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 107:10719–10724CrossRefGoogle Scholar
  18. Peng YJ, Makarenko VV, Nanduri J, Vasavda C, Raghuraman G, Yuan G, Gadalla MM, Kumar GK, Snyder SH, Prabhakar NR (2014) Inherent variations in CO-H2S-mediated carotid body O2 sensing mediate hypertension and pulmonary edema. Proc Natl Acad Sci U S A 111:1174–1179CrossRefGoogle Scholar
  19. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM (2013) Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177:1006–1014CrossRefGoogle Scholar
  20. Prabhakar NR, Peers C (2014) Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body. Physiology (Bethesda) 29:49–57Google Scholar
  21. Quan SF, Awad KM, Budhiraja R, Parthasarathy S (2012) The quest to improve CPAP adherence–PAP potpourri is not the answer. J Clin Sleep Med 8:49–50PubMedPubMedCentralGoogle Scholar
  22. St-Onge MP, Grandner MA, Brown D, Conroy MB, Jean-Louis G, Coons M, Bhatt DL, American Heart Association Obesity B. C., D.abetes, and Nutrition Committees of the Council on Lifestyle and Cardiometabolic Health, Young C. o. C. D. i. t., Cardiology C. o. C., Council a. S (2016) Sleep duration and quality: impact on lifestyle behaviors and cardiometabolic health: a scientific statement from the American Heart Association. Circulation 134:e367–e386CrossRefGoogle Scholar
  23. Veasey SC, Guilleminault C, Strohl KP, Sanders MH, Ballard RD, Magalang UJ (2006) Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 29:1036–1044CrossRefGoogle Scholar
  24. Xie A, Rutherford R, Rankin F, Wong B, Bradley TD (1995) Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med 152:1950–1955CrossRefGoogle Scholar
  25. Yamauchi M, Combs D, Parthasarathy S (2016) Adaptive servo-ventilation for central sleep apnea in heart failure. N Engl J Med 374:689PubMedGoogle Scholar
  26. 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:ra37CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ying-Jie Peng
    • 1
  • Xiuli Zhang
    • 1
  • Jayasri Nanduri
    • 1
  • Nanduri R. Prabhakar
    • 1
    Email author
  1. 1.Institute for Integrative Physiology and Center for Systems Biology of Oxygen Sensing, Biological Sciences DivisionUniversity of ChicagoChicagoUSA

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