Skip to main content
SpringerLink
Log in

From Physiological Redox Signalling to Oxidant Stress

  • Chapter
  • First Online:
Pulmonary Vasculature Redox Signaling in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 967))

Abstract

Oxidant stress is strongly associated with cardiovascular disease, including pulmonary hypertension, but antioxidant therapies have so far proven ineffective. This is partly due to a lack of understanding of the key role played by reactive oxygen species (ROS) in physiological cell signalling, and partly to the complex interrelationships between generators of ROS (e.g. mitochondria and NADPH oxidases, NOX), cellular antioxidant systems and indeed Ca2+ signalling. At physiological levels ROS reversibly affect the function of numerous enzymes and transcription factors, most often via oxidation of specific protein thiols. Importantly, they also affect pathways that promote ROS generation by NOX or mitochondria (ROS-induced ROS release), which has an inherent propensity for positive feedback and uncontrolled oxidant production. The reason this does not occur under normal conditions reflects in part a high level of compartmentalisation of ROS signalling within the cell, akin to that for Ca2+. This article considers the physiological processes which regulate NOX and mitochondrial ROS production and degradation and their interactions with each other and Ca2+ signalling pathways, and discusses how loss of spatiotemporal constraints and activation of positive feedback pathways may impact on their dysregulation in pulmonary hypertension.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

  1. Freund-Michel, V., Guibert, C., Dubois, M., Courtois, A., Marthan, R., Savineau, J. P., & Muller, B. (2013). Reactive oxygen species as therapeutic targets in pulmonary hypertension. Therapeutic Advances in Respiratory Disease, 7, 175–200.

    Article  PubMed  Google Scholar 

  2. Hansen, T., Galougahi, K. K., Celermajer, D., Rasko, N., Tang, O., Bubb, K. J., & Figtree, G. (2016). Oxidative and nitrosative signalling in pulmonary arterial hypertension - implications for development of novel therapies. Pharmacology & Therapeutics, 165, 50–62.

    Article  CAS  Google Scholar 

  3. Hood, K. Y., Montezano, A. C., Harvey, A. P., Nilsen, M., Maclean, M. R., & Touyz, R. M. (2016). Nicotinamide adenine dinucleotide phosphate oxidase-mediated redox signaling and vascular remodeling by 16alpha-hydroxyestrone in human pulmonary artery cells: Implications in pulmonary arterial hypertension. Hypertension, 68, 796–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tabima, D. M., Frizzell, S., & Gladwin, M. T. (2012). Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radical Biology & Medicine, 52, 1970–1986.

    Article  CAS  Google Scholar 

  5. Ghezzi, P., Jaquet, V., Marcucci, F., & Schmidt, H. H. (2016). The oxidative stress theory of disease: Levels of evidence and epistemological aspects. British Journal of Pharmacology, 174(12), 1784–1796.

    Article  PubMed  Google Scholar 

  6. Brown, D. I., & Griendling, K. K. (2015). Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circulation Research, 116, 531–549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Droge, W. (2002). Free radicals in the physiological control of cell function. Physiological Reviews, 82, 47–95.

    Article  CAS  PubMed  Google Scholar 

  8. Hlaing, K. H., & Clement, M. V. (2014). Formation of protein S-nitrosylation by reactive oxygen species. Free Radical Research, 48, 996–1010.

    Article  PubMed  Google Scholar 

  9. Knock, G. A., & Ward, J. P. (2011). Redox regulation of protein kinases as a modulator of vascular function. Antioxidants & Redox Signaling, 15, 1531–1547.

    Article  CAS  Google Scholar 

  10. Billaud, M., Lohman, A. W., Johnstone, S. R., Biwer, L. A., Mutchler, S., & Isakson, B. E. (2014). Regulation of cellular communication by signaling microdomains in the blood vessel wall. Pharmacological Reviews, 66, 513–569.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jones, D. P., & Go, Y. M. (2010). Redox compartmentalization and cellular stress. Diabetes, Obesity and Metabolism, 12(Suppl 2), 116–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kholodenko, B. N. (2006). Cell-signalling dynamics in time and space. Nature Reviews. Molecular Cell Biology, 7, 165–176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Winterbourn, C. C., & Hampton, M. B. (2008). Thiol chemistry and specificity in redox signaling. Free Radical Biology & Medicine, 45, 549–561.

    Article  CAS  Google Scholar 

  14. Konior, A., Schramm, A., Czesnikiewicz-Guzik, M., & Guzik, T. J. (2014). NADPH oxidases in vascular pathology. Antioxidants & Redox Signaling, 20, 2794–2814.

    Article  CAS  Google Scholar 

  15. Daiber, A., Di Lisa, F., Oelze, M., Kroller-Schon, S., Steven, S., Schulz, E., & Munzel, T. (2016). Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. British Journal of Pharmacology. doi:10.1111/bph.13403.

  16. Rathore, R., Zheng, Y.-M., Niu, C.-F., Liu, Q.-H., Korde, A., Ho, Y.-S., & Wang, Y. X. (2008). Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells. Free Radical Biology & Medicine, 45, 1223–1231.

    Article  CAS  Google Scholar 

  17. Shi, R., Hu, C., Yuan, Q., Yang, T., Peng, J., Li, Y., Bai, Y., Cao, Z., Cheng, G., & Zhang, G. (2011). Involvement of vascular peroxidase 1 in angiotensin II-induced vascular smooth muscle cell proliferation. Cardiovascular Research, 91, 27–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Weidinger, A., & Kozlov, A. V. (2015). Biological activities of reactive oxygen and nitrogen species: Oxidative stress versus signal transduction. Biomolecules, 5, 472–484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li, L., Feng, D., Luo, Z., Welch, W. J., Wilcox, C. S., & Lai, E. Y. (2015). Remodeling of afferent arterioles from mice with oxidative stress does not account for increased contractility but does limit excessive wall stress. Hypertension, 66, 550–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ramiro-Diaz, J. M., Giermakowska, W., Weaver, J. M., Jernigan, N. L., & Gonzalez Bosc, L. V. (2014). Mechanisms of NFATc3 activation by increased superoxide and reduced hydrogen peroxide in pulmonary arterial smooth muscle. American Journal of Physiology. Cell Physiology, 307, C928–C938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Knock, G. A., Snetkov, V. A., Shaifta, Y., Connolly, M., Drndarski, S., Noah, A., Pourmahram, G. E., Becker, S., Aaronson, P. I., & Ward, J. P. (2009). Superoxide constricts rat pulmonary arteries via rho-kinase-mediated Ca(2+) sensitization. Free Radical Biology & Medicine, 46, 633–642.

    Article  CAS  Google Scholar 

  22. Pourmahram, G. E., Snetkov, V. A., Shaifta, Y., Drndarski, S., Knock, G. A., Aaronson, P. I., & Ward, J. P. (2008). Constriction of pulmonary artery by peroxide: Role of Ca2+ release and PKC. Free Radical Biology & Medicine, 45, 1468–1476.

    Article  CAS  Google Scholar 

  23. Wong, C. M., Marcocci, L., Liu, L., & Suzuki, Y. J. (2010). Cell signaling by protein carbonylation and decarbonylation. Antioxidants & Redox Signaling, 12, 393–404.

    Article  CAS  Google Scholar 

  24. Gorlach, A., Bertram, K., Hudecova, S., & Krizanova, O. (2015). Calcium and ROS: A mutual interplay. Redox Biology, 6, 260–271.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ebrahimian, T., & Touyz, R. M. (2008). Thioredoxin in vascular biology: Role in hypertension. Antioxidants & Redox Signaling, 10, 1127–1136.

    Article  CAS  Google Scholar 

  26. Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology, 53, 401–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bedard, K., & Krause, K. H. (2007). The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiological Reviews, 87, 245–313.

    Article  CAS  PubMed  Google Scholar 

  28. Hodge, R. G., & Ridley, A. J. (2016). Regulating rho GTPases and their regulators. Nature Reviews. Molecular Cell Biology, 17, 496–510.

    Article  CAS  PubMed  Google Scholar 

  29. Diebold, L., & Chandel, N. S. (2016). Mitochondrial ROS regulation of proliferating cells. Free Radical Biology & Medicine, 100, 86–93.

    Article  CAS  Google Scholar 

  30. Sylvester, J. T., Shimoda, L. A., Aaronson, P. I., & Ward, J. P. (2012). Hypoxic pulmonary vasoconstriction. Physiological Reviews, 92, 367–520.

    Article  CAS  PubMed  Google Scholar 

  31. Li, J. M., & Shah, A. M. (2003). Mechanism of endothelial cell NADPH oxidase activation by angiotensin II. Role of the p47phox subunit. The Journal of Biological Chemistry, 278, 12094–12100.

    Article  CAS  PubMed  Google Scholar 

  32. Lemmon, M. A., & Schlessinger, J. (2010). Cell signaling by receptor tyrosine kinases. Cell, 141, 1117–1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosenbaum, D. M., Rasmussen, S. G., & Kobilka, B. K. (2009). The structure and function of G-protein-coupled receptors. Nature, 459, 356–363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, X., Chattopadhyay, A., Ji, Q. S., Owen, J. D., Ruest, P. J., Carpenter, G., & Hanks, S. K. (1999). Focal adhesion kinase promotes phospholipase C-gamma1 activity. Proceedings of the National Academy of Sciences of the United States of America, 96, 9021–9026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Knock, G. A. (2015). Tyrosine kinases as key modulators of smooth muscle function in health and disease. The Journal of Physiology, 593, 3805–3806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ohanian, J., Pieri, M., & Ohanian, V. (2015). Non-receptor tyrosine kinases and the actin cytoskeleton in contractile vascular smooth muscle. The Journal of Physiology, 593, 3807–3814.

    Article  CAS  PubMed  Google Scholar 

  37. Shaifta, Y., Snetkov, V. A., Prieto-Lloret, J., Knock, G. A., Smirnov, S. V., Aaronson, P. I., & Ward, J. P. (2015). Sphingosylphosphorylcholine potentiates vasoreactivity and voltage-gated Ca2+ entry via NOX1 and reactive oxygen species. Cardiovascular Research, 106, 121–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chakraborti, S., Chowdhury, A., Kar, P., Das, P., Shaikh, S., Roy, S., & Chakraborti, T. (2009). Role of protein kinase C in NADPH oxidase derived O2*(−)-mediated regulation of KV-LVOCC axis under U46619 induced increase in [Ca2+]i in pulmonary smooth muscle cells. Archives of Biochemistry and Biophysics, 487, 123–130.

    Article  CAS  PubMed  Google Scholar 

  39. Wedgwood, S., Dettman, R. W., & Black, S. M. (2001). ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. American Journal of Physiology. Lung Cellular and Molecular Physiology, 281, L1058–L1067.

    CAS  PubMed  Google Scholar 

  40. Spencer, N. Y., & Engelhardt, J. F. (2014). The basic biology of redoxosomes in cytokine-mediated signal transduction and implications for disease-specific therapies. Biochemistry, 53, 1551–1564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Han, D., Antunes, F., Canali, R., Rettori, D., & Cadenas, E. (2003). Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. The Journal of Biological Chemistry, 278, 5557–5563.

    Article  CAS  PubMed  Google Scholar 

  42. Mumbengegwi, D. R., Li, Q., Li, C., Bear, C. E., & Engelhardt, J. F. (2008). Evidence for a superoxide permeability pathway in endosomal membranes. Molecular and Cellular Biology, 28, 3700–3712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, F., Jin, S., Yi, F., Xia, M., Dewey, W. L., & Li, P. L. (2008). Local production of O2- by NAD(P)H oxidase in the sarcoplasmic reticulum of coronary arterial myocytes: cADPR-mediated Ca2+ regulation. Cellular Signalling, 20, 637–644.

    Article  CAS  PubMed  Google Scholar 

  44. Willems, P. H., Rossignol, R., Dieteren, C. E., Murphy, M. P., & Koopman, W. J. (2015). Redox homeostasis and mitochondrial dynamics. Cell Metabolism, 22, 207–218.

    Article  CAS  PubMed  Google Scholar 

  45. Adesina, S. E., Kang, B. Y., Bijli, K. M., MA, J., Cheng, J., Murphy, T. C., Michael Hart, C., & Sutliff, R. L. (2015). Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radical Biology & Medicine, 87, 36–47.

    Article  CAS  Google Scholar 

  46. Waypa, G. B., Chandel, N. S., & Schumacker, P. T. (2001). Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circulation Research, 88, 1259–1266.

    Article  CAS  PubMed  Google Scholar 

  47. Mackay, C. E., & Knock, G. A. (2015). Control of vascular smooth muscle function by Src-family kinases and reactive oxygen species in health and disease. The Journal of Physiology, 593, 3815–3828.

    Article  CAS  PubMed  Google Scholar 

  48. Yadav, V. R., Song, T., Joseph, L., Mei, L., Zheng, Y. M., & Wang, Y. X. (2013). Important role of PLC-gamma1 in hypoxic increase in intracellular calcium in pulmonary arterial smooth muscle cells. American Journal of Physiology. Lung Cellular and Molecular Physiology, 304, L143–L151.

    Article  CAS  PubMed  Google Scholar 

  49. Zinkevich, N. S., & Gutterman, D. D. (2011). ROS-induced ROS release in vascular biology: Redox-redox signaling. American Journal of Physiology. Heart and Circulatory Physiology, 301, H647–H653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Davidson, S. M., & Duchen, M. R. (2006). Calcium microdomains and oxidative stress. Cell Calcium, 40, 561–574.

    Article  CAS  PubMed  Google Scholar 

  51. Chen, F., Barman, S., Yu, Y., Haigh, S., Wang, Y., Black, S. M., Rafikov, R., Dou, H., Bagi, Z., Han, W., Su, Y., & Fulton, D. J. (2014). Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species. Free Radical Biology & Medicine, 73, 201–213.

    Article  CAS  Google Scholar 

  52. Hilenski, L. L., Clempus, R. E., Quinn, M. T., Lambeth, J. D., & Griendling, K. K. (2004). Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 677–683.

    Article  CAS  PubMed  Google Scholar 

  53. Chaplin, N. L., Nieves-Cintron, M., Fresquez, A. M., Navedo, M. F., & Amberg, G. C. (2015). Arterial smooth muscle mitochondria amplify hydrogen peroxide microdomains functionally coupled to L-type calcium channels. Circulation Research, 117, 1013–1023.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Amberg, G. C., Earley, S., & Glapa, S. A. (2010). Local regulation of arterial L-type calcium channels by reactive oxygen species. Circulation Research, 107, 1002–1010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Snetkov, V. A., Thomas, G. D., Teague, B., Leach, R. M., Shaifta, Y., Knock, G. A., Aaronson, P. I., & Ward, J. P. (2008). Low concentrations of sphingosylphosphorylcholine enhance pulmonary artery vasoreactivity: The role of protein kinase C delta and Ca2+ entry. Hypertension, 51, 239–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rowlands, D. J. (2016). Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander? Pharmacology & Therapeutics, 166, 96–105.

    Article  CAS  Google Scholar 

  57. Murphy, M. P. (2012). Modulating mitochondrial intracellular location as a redox signal. Science Signalling, 5, pe39.

    Google Scholar 

Download references

Acknowledgements

I would like to thank GA Knock, PI Aaronson, VA Snetkov and Y Shaifta for their contributions to our work referenced in this chapter. Funded by the Wellcome Trust grant #087776 and British Heart Foundation.

Author information

Authors and Affiliations

  1. Division of Asthma, Allergy, and Lung Biology, King’s College London, 5th Floor Tower Wing, Guy’s Campus, London, SE1 9RT, UK

    Jeremy P. T. Ward

Authors
  1. Jeremy P. T. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy P. T. Ward .

Editor information

Editors and Affiliations

  1. Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, USA

    Yong-Xiao Wang

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Ward, J.P.T. (2017). From Physiological Redox Signalling to Oxidant Stress. In: Wang, YX. (eds) Pulmonary Vasculature Redox Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 967. Springer, Cham. https://doi.org/10.1007/978-3-319-63245-2_21

Download citation

Publish with us

Policies and ethics

Search

Navigation