Skip to main content

Hypoxia Regulates MicroRNA Expression in the Human Carotid Body

  • Conference paper
  • First Online:
Arterial Chemoreceptors

Abstract

How hypoxia regulates gene expression in the human carotid body (CB) remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the impact of important post-transcriptional regulators, such as non-coding RNAs, and in particular miRNAs is not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Bishop T, Talbot NP, Turner PJ, Nicholls LG, Pascual A, Hodson EJ, Douglas G, Fielding JW, Smith TG, Demetriades M, Schofield CJ, Robbins PA, Pugh CW, Buckler KJ, Ratcliffe PJ (2013) Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2. J Physiol 591:3565–3577

    Article  CAS  Google Scholar 

  • Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–192

    Article  CAS  Google Scholar 

  • Bruning U, Cerone L, Neufeld Z, Fitzpatrick SF, Cheong A, Scholz CC, Simpson DA, Leonard MO, Tambuwala MM, Cummins EP, Taylor CT (2011) MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia. Mol Cell Biol 31:4087–4096

    Article  CAS  Google Scholar 

  • Chan SY, Loscalzo J (2010) MicroRNA-210: a unique and pleiotropic hypoxamir. Cell Cycle 9:1072–1083

    Article  CAS  Google Scholar 

  • Chen Y, Zhang Z, Luo C, Chen Z, Zhou J (2016) MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1alpha-mediated glycolysis. Oncol Rep 36:471–479

    Article  CAS  Google Scholar 

  • Helwak A, Kudla G, Dudnakova T, Tollervey D (2013) Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell 153:654–665

    Article  CAS  Google Scholar 

  • Hempleman SC, Warburton SJ (2013) Comparative embryology of the carotid body. Respir Physiol Neurobiol 185:3–8

    Article  Google Scholar 

  • Hodson EJ, Nicholls LG, Turner PJ, Llyr R, Fielding JW, Douglas G, Ratnayaka I, Robbins PA, Pugh CW, Buckler KJ, Ratcliffe PJ, Bishop T (2016) Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway. J Physiol 594:1179–1195

    Article  CAS  Google Scholar 

  • Iturriaga R, Alcayaga J (2004) Neurotransmission in the carotid body: transmitters and modulators between glomus cells and petrosal ganglion nerve terminals. Brain Res Brain Res Rev 47:46–53

    Article  CAS  Google Scholar 

  • Kahlin J, Mkrtchian S, Ebberyd A, Hammarstedt-Nordenvall L, Nordlander B, Yoshitake T, Kehr J, Prabhakar N, Poellinger L, Fagerlund MJ, Eriksson LI (2014) The human carotid body releases acetylcholine, ATP and cytokines during hypoxia. Exp Physiol 99:1089–1098

    Article  CAS  Google Scholar 

  • Kay JM, Laidler P (1977) Hypoxia and the carotid body. J Clin Pathol Suppl (R Coll Pathol) 11:30–44

    Article  CAS  Google Scholar 

  • Kole AJ, Swahari V, Hammond SM, Deshmukh M (2011) miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis. Genes Dev 25:125–130

    Article  CAS  Google Scholar 

  • Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, Calin GA, Ivan M (2007) A microRNA signature of hypoxia. Mol Cell Biol 27:1859–1867

    Article  CAS  Google Scholar 

  • Lopez-Barneo J, Gonzalez-Rodriguez P, Gao L, Fernandez-Aguera MC, Pardal R, Ortega-Saenz P (2016) Oxygen sensing by the carotid body: mechanisms and role in adaptation to hypoxia. Am J Physiol Cell Physiol 310:C629–C642

    Article  Google Scholar 

  • Loscalzo J (2010) The cellular response to hypoxia: tuning the system with microRNAs. J Clin Invest 120:3815–3817

    Article  CAS  Google Scholar 

  • Ludwig N, Leidinger P, Becker K, Backes C, Fehlmann T, Pallasch C, Rheinheimer S, Meder B, Stahler C, Meese E, Keller A (2016) Distribution of miRNA expression across human tissues. Nucleic Acids Res 44:3865–3877

    Article  CAS  Google Scholar 

  • Mkrtchian S, Kahlin J, Ebberyd A, Gonzalez C, Sanchez D, Balbir A, Kostuk EW, Shirahata M, Fagerlund MJ, Eriksson LI (2012) The human carotid body transcriptome with focus on oxygen sensing and inflammation--a comparative analysis. J Physiol 590:3807–3819

    Article  CAS  Google Scholar 

  • Nallamshetty S, Chan SY, Loscalzo J (2013) Hypoxia: a master regulator of microRNA biogenesis and activity. Free Radic Biol Med 64:20–30

    Article  CAS  Google Scholar 

  • Nowak JS, Michlewski G (2013) miRNAs in development and pathogenesis of the nervous system. Biochem Soc Trans 41:815–820

    Article  CAS  Google Scholar 

  • Ortega-Saenz P, Pardal R, Levitsky K, Villadiego J, Munoz-Manchado AB, Duran R, Bonilla-Henao V, Arias-Mayenco I, Sobrino V, Ordonez A, Oliver M, Toledo-Aral JJ, Lopez-Barneo J (2013) Cellular properties and chemosensory responses of the human carotid body. J Physiol 591:6157–6173

    Article  CAS  Google Scholar 

  • Pepper DR, Landauer RC, Kumar P (1995) Postnatal development of CO2-O2 interaction in the rat carotid body in vitro. J Physiol 485(Pt 2):531–541

    Article  CAS  Google Scholar 

  • Poellinger L, Johnson RS (2004) HIF-1 and hypoxic response: the plot thickens. Curr Opin Genet Dev 14:81–85

    Article  CAS  Google Scholar 

  • Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611

    Article  CAS  Google Scholar 

  • Saldana MJ, Salem LE, Travezan R (1973) High altitude hypoxia and chemodectomas. Hum Pathol 4:251–263

    Article  CAS  Google Scholar 

  • Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA, Croce CM (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082–5089

    Article  CAS  Google Scholar 

  • Wilczynska A, Bushell M (2015) The complexity of miRNA-mediated repression. Cell Death Differ 22:22–33

    Article  CAS  Google Scholar 

  • Williams Z, Ben-Dov IZ, Elias R, Mihailovic A, Brown M, Rosenwaks Z, Tuschl T (2013) Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc Natl Acad Sci U S A 110:4255–4260

    Article  CAS  Google Scholar 

  • Zhu C, Zhou R, Zhou Q, Chang Y, Jiang M (2016) microRNA-539 suppresses tumor growth and tumorigenesis and overcomes arsenic trioxide resistance in hepatocellular carcinoma. Life Sci 166:34–40

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by research grants from the Research Council for Medicine, Sweden, Stockholm County Council, Thorsten Söderberg Research Foundation, Gösta Fraenckels Foundation, Jeanssons Foundation, Tore Nilsons Fundation, Magnus Bergvalls Foundation, Capio Foundation, LPS Medical, Karolinska Institutet Funds and The Swedish Society for Medicine, all from Stockholm, Sweden.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Souren Mkrtchian .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Mkrtchian, S. et al. (2018). Hypoxia Regulates MicroRNA Expression in the Human Carotid Body. In: Gauda, E., Monteiro, M., Prabhakar, N., Wyatt, C., Schultz, H. (eds) Arterial Chemoreceptors. Advances in Experimental Medicine and Biology, vol 1071. Springer, Cham. https://doi.org/10.1007/978-3-319-91137-3_3

Download citation

Publish with us

Policies and ethics