Skip to main content
SpringerLink
Log in

Oxidative Stress in Pulmonary Artery Hypertension

  • Chapter
  • First Online:
Modulation of Oxidative Stress in Heart Disease

  • 346 Accesses

Abstract

Pulmonary artery hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling ultimately leading to right ventricular failure and death. The last few decades have seen considerable progress in PAH therapy based on drugs targeting three major mechanistic pathways, viz., prostacyclin, endothelin and nitric oxide pathways. A growing body of research has documented that “oxidative stress” is intricately associated with development of PAH. Experimental studies have shown that markers of oxidative tissue damage are present in different genetic and chemical models of PAH. Animal studies have also shown the preventive and therapeutic potential of endogenous antioxidants and/or drugs with antioxidant activity in experimental PAH. Though the evidence implicating oxidative stress in PAH has also been generated in human PAH studies, the clinical trials of antioxidants have not yet yielded encouraging results. Further studies are warranted to unravel the reason(s) underlying this paradox in order to develop potential curative drugs for this morbid disorder.

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 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

  1. Simonneau G, Gatzoulis MA, Adatia I et al (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 62:D34–D41

    Article  PubMed  Google Scholar 

  2. D’Alonzo GE, Barst RJ, Ayres SM et al (1991) Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115:343–349

    Article  PubMed  Google Scholar 

  3. Humbert M, Sitbon O, Simonneau G (2004) Treatment of pulmonary arterial hypertension. N Engl J Med 351:1425–1436

    Article  CAS  PubMed  Google Scholar 

  4. Menon S (2009) Pulmonary hypertension in the south east Asia region: an analysis of indexed publication profile. PVRI Rev 1:167

    Article  Google Scholar 

  5. Humbert M, Morrell NW, Archer SL et al (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S–24S

    Article  CAS  PubMed  Google Scholar 

  6. Badlam JB, Bull TM (2017) Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities. Ther Adv Chronic Dis 8:47–64

    Article  PubMed  PubMed Central  Google Scholar 

  7. Christman BW, McPherson CD, Newman JH et al (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327:70–75

    Article  CAS  PubMed  Google Scholar 

  8. Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351:1655–1665

    Article  CAS  PubMed  Google Scholar 

  9. Bruderer S, Hurst N, Remenova T, Dingemanse J (2017) Clinical pharmacology, efficacy, and safety of selexipag for the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf 16:743–751

    Article  CAS  PubMed  Google Scholar 

  10. Sidharta PN, Treiber A, Dingemanse J (2015) Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet 54:457–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ghofrani H-A, Galiè N, Grimminger F et al (2013) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369:330–340

    Article  CAS  PubMed  Google Scholar 

  12. Wong C-M, Bansal G, Pavlickova L et al (2013) Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid Redox Signal 18:1789–1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pagel J-I, Deindl E (2012) Disease progression mediated by egr-1 associated signaling in response to oxidative stress. Int J Mol Sci 13:13104–13117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wolin MS, Ahmad M, Gupte SA (2005) The sources of oxidative stress in the vessel wall. Kidney Int 67:1659–1661

    Article  CAS  PubMed  Google Scholar 

  15. Mohazzab KM, Wolin MS (1994) Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol 267:L815–L822

    CAS  PubMed  Google Scholar 

  16. Terada LS, Guidot DM, Leff JA et al (1992) Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci USA 89:3362–3366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Grobe AC, Wells SM, Benavidez E et al (2006) Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase. Am J Physiol Lung Cell Mol Physiol 290:L1069–L1077

    Article  CAS  PubMed  Google Scholar 

  18. Cai H, Griendling KK, Harrison DG (2003) The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 24:471–478

    Article  CAS  PubMed  Google Scholar 

  19. McNally JS, Davis ME, Giddens DP et al (2003) Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol 285:H2290–H2297

    Article  CAS  PubMed  Google Scholar 

  20. Mittal M, Roth M, König P et al (2007) Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101:258–267

    Article  CAS  PubMed  Google Scholar 

  21. Li S, Tabar SS, Malec V et al (2008) NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts. Antioxid Redox Signal 10:1687–1698

    Article  CAS  PubMed  Google Scholar 

  22. Csiszar A, Labinskyy N, Olson S et al (2009) Resveratrol prevents monocrotaline-induced pulmonary hypertension in rats. Hypertension 54:668–675

    Article  CAS  PubMed  Google Scholar 

  23. Wang X, Yang Y, Yang D et al (2016) Tetrandrine prevents monocrotaline-induced pulmonary arterial hypertension in rats through regulation of the protein expression of inducible nitric oxide synthase and cyclic guanosine monophosphate-dependent protein kinase type 1. J Vasc Surg 64:1468–1477

    Article  PubMed  Google Scholar 

  24. Farahmand F, Hill MF, Singal PK (2004) Antioxidant and oxidative stress changes in experimental cor pulmonale. Mol Cell Biochem 260:21–29

    Article  PubMed  Google Scholar 

  25. Nisbet RE, Graves AS, Kleinhenz DJ et al (2009) The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice. Am J Respir Cell Mol Biol 40:601–609

    Article  CAS  PubMed  Google Scholar 

  26. Araneda OF, Tuesta M (2012) Lung oxidative damage by hypoxia. Oxid Med Cell Longev 2012:856918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao Y-Y, Zhao YD, Mirza MK et al (2009) Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 119:2009–2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Konduri GG, Bakhutashvili I, Eis A, Pritchard K (2007) Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 292:H1812–H1820

    Article  CAS  PubMed  Google Scholar 

  29. Liu JQ, Zelko IN, Erbynn EM et al (2006) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290:L2–L10

    Article  CAS  PubMed  Google Scholar 

  30. Maniatis NA, Shinin V, Schraufnagel DE et al (2008) Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1-/- mice. Am J Physiol Lung Cell Mol Physiol 294:L865–L873

    Article  CAS  PubMed  Google Scholar 

  31. Kamezaki F, Tasaki H, Yamashita K et al (2008) Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats. Am J Respir Crit Care Med 177:219–226

    Article  CAS  PubMed  Google Scholar 

  32. Farrow KN, Lakshminrusimha S, Reda WJ et al (2008) Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 295:L979–L987

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Galhotra P, Prabhakar P, Meghwani H et al (2018) Beneficial effects of fenofibrate in pulmonary hypertension in rats. Mol Cell Biochem. https://doi.org/10.1007/s11010-018-3355-3

    Article  CAS  PubMed  Google Scholar 

  34. Meghwani H, Prabhakar P, Mohammed SA et al (2018) Beneficial effect of ocimum sanctum (Linn) against monocrotaline-induced pulmonary hypertension in rats. Med Basel Switz 5. https://doi.org/10.3390/medicines5020034

    Article  PubMed Central  CAS  Google Scholar 

  35. Meghwani H, Prabhakar P, Mohammed SA et al (2017) Beneficial effects of aqueous extract of stem bark of Terminalia arjuna (Roxb.), An ayurvedic drug in experimental pulmonary hypertension. J Ethnopharmacol 197:184–194

    Article  PubMed  Google Scholar 

  36. Jankov RP, Kantores C, Pan J, Belik J (2008) Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 294:L233–L245

    Article  CAS  PubMed  Google Scholar 

  37. Wong C-M, Preston IR, Hill NS, Suzuki YJ (2012) Iron chelation inhibits the development of pulmonary vascular remodeling. Free Radic Biol Med 53:1738–1747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ghasemzadeh N, Patel RS, Eapen DJ et al (2014) Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertens Dallas Tex 63:1270–1275

    Article  CAS  Google Scholar 

  39. Cracowski J-L, Degano B, Chabot F et al (2012) Independent association of urinary F2-isoprostanes with survival in pulmonary arterial hypertension. Chest 142:869–876

    Article  CAS  PubMed  Google Scholar 

  40. Spiekermann S, Schenk K, Hoeper MM (2009) Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur Respir J 34:276

    Article  CAS  PubMed  Google Scholar 

  41. Masri FA, Comhair SAA, Dostanic-Larson I et al (2008) Deficiency of lung antioxidants in idiopathic pulmonary arterial hypertension. Clin Transl Sci 1:99–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bowers R, Cool C, Murphy RC et al (2004) Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 169:764–769

    Article  PubMed  Google Scholar 

  43. Dani C, Poggi C (2014) The role of genetic polymorphisms in antioxidant enzymes and potential antioxidant therapies in neonatal lung disease. Antioxid Redox Signal 21:1863–1880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peña-Silva RA, Miller JD, Chu Y, Heistad DD (2009) Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves. Am J Physiol Heart Circ Physiol 297:H1354–H1360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Semen K, Yelisyeyeva O, Jarocka-Karpowicz I et al (2015) Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability. Redox Biol 7:48–57

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Fan Y-F, Zhang R, Jiang X et al (2013) The phosphodiesterase-5 inhibitor vardenafil reduces oxidative stress while reversing pulmonary arterial hypertension. Cardiovasc Res 99:395–403

    Article  CAS  PubMed  Google Scholar 

  47. Gabrielli LA, Castro PF, Godoy I et al (2011) Systemic oxidative stress and endothelial dysfunction is associated with an attenuated acute vascular response to inhaled prostanoid in pulmonary artery hypertension patients. J Card Fail 17:1012–1017

    Article  CAS  PubMed  Google Scholar 

  48. Sharp J, Farha S, Park MM et al (2014) Coenzyme Q supplementation in pulmonary arterial hypertension. Redox Biol 2:884–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zeng W-J, Xiong C-M, Zhao L et al (2012) Atorvastatin in Pulmonary Arterial Hypertension (APATH) study. Eur Respir J 40:67–74

    Article  CAS  PubMed  Google Scholar 

  50. Kawut SM, Bagiella E, Lederer DJ et al (2011) Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension. Circulation 123:2985–2993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rysz-Górzynska M, Gluba-Brzózka A, Sahebkar A et al (2016) Efficacy of statin therapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Sci Rep 6:30060

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Rai PR, Cool CD, King JAC et al (2008) The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 178:558–564

    Article  PubMed  PubMed Central  Google Scholar 

  53. Xu W, Koeck T, Lara AR et al (2007) Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA 104:1342–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Govt. T. D. Medical College, Alappuzha, Alappuzha, Kerala, India

    Vinu Wilson

  2. Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India

    Subir Kumar Maulik

Authors
  1. Vinu Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Subir Kumar Maulik
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. Institute of Cardiovascular Science, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada

    Naranjan S. Dhalla

  3. Translational Health Science and Technology Institute, Faridabad, Haryana, India

    Madhu Dikshit

  4. Translational Health Science and Technology Institute, Faridabad, Haryana, India

    Nirmal K. Ganguly

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wilson, V., Maulik, S.K. (2019). Oxidative Stress in Pulmonary Artery Hypertension. In: Chakraborti, S., Dhalla, N., Dikshit, M., Ganguly, N. (eds) Modulation of Oxidative Stress in Heart Disease. Springer, Singapore. https://doi.org/10.1007/978-981-13-8946-7_16

Download citation

Publish with us

Policies and ethics

Search

Navigation