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Pulmonary Hypertension and the Right Ventricle: The Roles of Mitochondrial Reactive Oxygen Species in Causing Further Right Ventricular Mitochondrial Changes

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Oxidative Stress in Heart Diseases

Abstract

Pulmonary hypertension (PH) is a fatal disorder that is gaining considerable attention as an imminent global health concern. It is defined as an elevated mean pulmonary arterial pressure of ≥25 mm Hg at rest, while its pathogenesis is not well understood due to the involvement of complex molecular pathways. These pathways generally lead to pulmonary arterial smooth muscle cell proliferation, endothelial cell resistance to apoptosis, and vasoconstriction. These processes obliterate the lumens of pulmonary arterioles and thus increases mean pulmonary arterial pressure. This results in elevated right ventricular (RV) afterload that puts in motion a range of RV changes, in particular, RV mitochondrial changes. Of note, PH affects the RV in such a manner that RV mitochondria produce excessive reactive oxygen species (ROS). In this chapter, the roles of RV mitochondrial ROS in PH related RV failure are comprehensively discussed. Accumulating evidence is critically reviewed in relation to the impact of mitochondrial ROS on (a) RV remodelling, (b) RV mitochondrial gene expression and dynamics, and (b) RV mitochondrial respiration.

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References

  1. Galie N et al (2016) 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37(1):67–119

    Article  PubMed  Google Scholar 

  2. Maarman GJ et al (2017) Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature. Br J Pharmacol 174(7):497–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hoeper MM et al (2016) A global view of pulmonary hypertension. Lancet Respir Med 4(4):306–322

    Article  PubMed  Google Scholar 

  4. Mocumbi AO, Thienemann F, Sliwa K (2015) A global perspective on the epidemiology of pulmonary hypertension. Can J Cardiol 31(4):375–381

    Article  PubMed  Google Scholar 

  5. Kharsany AB, Karim QA (2016) HIV infection and aids in Sub-Saharan Africa: current status, challenges and opportunities. Open AIDS J 10:34–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sliwa K et al (2008) Spectrum of heart disease and risk factors in a black urban population in South Africa (the heart of Sowe to study): a cohort study. Lancet 371(9616):915–922

    Article  PubMed  Google Scholar 

  7. Thienemann F et al (2016) The causes, treatment, and outcome of pulmonary hypertension in Africa: insights from the pan African pulmonary hypertension cohort (PAPUCO) registry. Int J Cardiol 221:205–211

    Article  PubMed  Google Scholar 

  8. Gomberg-Maitland M, Michelakis ED (2010) A global pulmonary arterial hypertension registry: is it needed? Is it feasible? Pulmonary vascular disease: the global perspective. Chest 137(6):95s–101s

    Article  PubMed  Google Scholar 

  9. Maron BA, Loscalzo J (2013) Pulmonary hypertension: pathophysiology and signaling pathways. Handb Exp Pharmacol 218:31–58

    Article  CAS  PubMed  Google Scholar 

  10. Noordegraaf AV, Westerhof BE, Westerhof N (2017) Y the relationship between the right ventricle and its load in pulmonary hypertension. J Am Coll Cardiol 69(2):236–243

    Article  Google Scholar 

  11. Naeije R, Brimioulle S, Dewachter L (2014) Biomechanics of the right ventricle in health and disease (2013 grover conference series). Pulm Circ 4(3):395–406

    Article  PubMed  PubMed Central  Google Scholar 

  12. Penny DJ, Redington AN (2016) Function of the left and right ventricles and the interactions between them. Pediatr Crit Care Med 17(8):S112–S118

    Article  PubMed  Google Scholar 

  13. Opie LH et al (2006) Controversies in ventricular remodelling. Lancet 367(9507):356–367

    Article  PubMed  Google Scholar 

  14. Vonk-Noordegraaf A et al (2013) Right heart adaptation to pulmonary arterial hypertension physiology and pathobiology. J Am Coll Cardiol 62(25):D22–D33

    Article  PubMed  Google Scholar 

  15. Fulton DJR et al (2017) Reactive oxygen and nitrogen species in the development of pulmonary hypertension. Antioxidants 6(3):E54

    Article  CAS  PubMed  Google Scholar 

  16. Jernigan NL et al (2017) Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension. PLoS One 12(6):e0180455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Robin ED, Wong R (1988) Mitochondrial-DNA molecules and virtual number of mitochondria per cell in mammalian-cells. J Cell Physiol 136(3):507–513

    Article  CAS  PubMed  Google Scholar 

  18. Zorov DB, Juhaszova M, Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ros release. Physiol Rev 94(3):909–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zorov DB et al (2000) Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 192(7):1001–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Murphy E et al (2016) Mitochondrial function, biology, and role in disease. A scientific statement from the American Heart Association. Circ Res 118(12):1960–1991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rosca MG, Hoppel CL (2013) Mitochondrial dysfunction in heart failure. Heart Fail Rev 18(5):607–622. https://doi.org/10.1007/s10741-012-9340-0

    Article  CAS  PubMed  Google Scholar 

  22. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  CAS  PubMed  Google Scholar 

  23. Camello-Almaraz C et al (2006) Mitochondrial reactive oxygen species and Ca2+ signaling. Am J Phys Cell Phys 291(5):C1082–C1088

    Article  CAS  Google Scholar 

  24. Birben E et al (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5(1):9–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kelley EE et al (2010) Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic Biol Med 48(4):493–498

    Article  CAS  PubMed  Google Scholar 

  26. Vergeade A et al (2012) Xanthine oxidase contributes to mitochondrial ROS generation in an experimental model of cocaine-induced diastolic dysfunction. J Cardiovasc Pharmacol 60(6):538–543

    Article  CAS  PubMed  Google Scholar 

  27. Dikalov S et al (2011) Crosstalk between mitochondrial ROS and NADPH oxidases in cardiovascular and degenerative diseases: application of mitochondria-targeted antioxidants. Free Radic Biol Med 51:S85–S86

    Article  Google Scholar 

  28. Zorov DB et al (2001) Mechanisms of “reactive oxygen species (ROS)-induced ROS release” during induction of the mitochondrial permeability transition (MPT). Biophys J 80(1):500a–500a

    Google Scholar 

  29. Gnaiger E (2014) Mitochondrial pathways and respiratory control, an introduction to oxphos analysis, 4th edn. OROBOROS MiPNet Publications, Innsbruck

    Google Scholar 

  30. Grivennikova VG, Vinogradov AD (2013) Mitochondrial production of reactive oxygen species. Biochemistry (Mosc) 78(13):1490–1511

    Article  CAS  Google Scholar 

  31. Maarman GJ (2017) Natural antioxidants as potential therapy, and a promising role for melatonin against pulmonary hypertension. Adv Exp Med Biol 967:161–178

    Article  CAS  PubMed  Google Scholar 

  32. Wong CM et al (2013) Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid Redox Signal 18(14):1789–1796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Adesina SE et al (2015) Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med 87:36–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maarman G et al (2015) Melatonin as a preventive and curative therapy against pulmonary hypertension. J Pineal Res 59(3):343–353

    Article  CAS  PubMed  Google Scholar 

  35. Zuo L et al (2014) Molecular characterization of reactive oxygen species in systemic and pulmonary hypertension. Am J Hypertens 27(5):643–650

    Article  CAS  PubMed  Google Scholar 

  36. Irodova NL et al (2002) Oxidative stress in patients with primary pulmonary hypertension. Bull Exp Biol Med 133(6):580–582

    Article  CAS  PubMed  Google Scholar 

  37. Spiekermann S, Schenk K, Hoeper MM (2009) Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur Respir J 34(1):276

    Article  CAS  PubMed  Google Scholar 

  38. Zhang S et al (2015) Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study. BMC Pulm Med 15:50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Reis GS et al (2013) Oxidative-stress biomarkers in patients with pulmonary hypertension. Pulm Circ 3(4):856–861

    Article  PubMed  PubMed Central  Google Scholar 

  40. Leichsenring-Silva F et al (2011) Association of the time course of pulmonary arterial hypertension with changes in oxidative stress in the left ventricle. Clin Exp Pharmacol Physiol 38(12):804–810

    Article  CAS  PubMed  Google Scholar 

  41. Redout EM et al (2010) Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure. Am J Phys Heart Circ Phys 298(3):H1038–H1047

    CAS  Google Scholar 

  42. Redout EM et al (2007) Right-ventricular failure is associated with increased mitochondrial complex ii activity and production of reactive oxygen species. Cardiovasc Res 75(4):770–781

    Article  CAS  PubMed  Google Scholar 

  43. Lu X et al (2011) Elevated oxidative stress and endothelial dysfunction in right coronary artery of right ventricular hypertrophy. J Appl Physiol 110(6):1674–1681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rabilloud T et al (2001) The mitochondrial antioxidant defence system and its response to oxidative stress. Proteomics 1(9):1105–1110

    Article  CAS  PubMed  Google Scholar 

  45. Lijnen PJ, van Pelt JF, Fagard RH (2012) Stimulation of reactive oxygen species and collagen synthesis by angiotensin II in cardiac fibroblasts. Cardiovasc Ther 30(1):e1–e8

    Article  CAS  PubMed  Google Scholar 

  46. Moris D et al (2017) The role of reactive oxygen species in the pathophysiology of cardiovascular diseases and the clinical significance of myocardial redox. Ann Transl Med 5(16):326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Aguero J et al (2014) Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model. Am J Phys Heart Circ Phys 307(8):H1204–H1215

    CAS  Google Scholar 

  48. Naeije R, Manes A (2014) The right ventricle in pulmonary arterial hypertension. Eur Respir Rev 23(134):476–487

    Article  PubMed  Google Scholar 

  49. Rain S et al (2016) Right ventricular myocardial stiffness in experimental pulmonary arterial hypertension relative contribution of fibrosis and myofibril stiffness. Circ Heart Fail 9(7):e002636

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ryan JJ, Archer SL (2014) The right ventricle in pulmonary arterial hypertension disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res 115(1):176–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Richter K, Kietzmann T (2016) Reactive oxygen species and fibrosis: further evidence of a significant liaison. Cell Tissue Res 365(3):591–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Buermans HPJ et al (2005) Microarray analysis reveals pivotal divergent MRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 21(3):314–323

    Article  CAS  PubMed  Google Scholar 

  53. Pearce SF et al (2017) Regulation of mammalian mitochondrial gene expression: recent advances. Trends Biochem Sci 42(8):625–639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gomez-Arroyo J et al (2013) Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy secondary to pulmonary arterial hypertension. Circ Heart Fail 6(1):136–144

    Article  CAS  PubMed  Google Scholar 

  55. Enache I et al (2013) Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension. Mol Cell Biochem 373(1–2):161–170

    Article  CAS  PubMed  Google Scholar 

  56. Cantó C, Auwerx J (2009) Pgc-1alpha, sirt1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20(2):98–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rowe GC, Jiang A, Arany Z (2010) Pgc-1 coactivators in cardiac development and disease. Circ Res 107(7):825–838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Larsen S et al (2012) Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol 590(14):3349–3360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ong SB et al (2015) Mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease. Eur J Pharmacol 763:104–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sharp WW, Archer SL (2015) Mitochondrial dynamics in cardiovascular disease: fission and fusion foretell form and function. J Mol Med 93(3):225–228

    Article  PubMed  Google Scholar 

  61. Song MS et al (2014) Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy. Circ Res 115(3):348–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen L et al (2009) Mitochondrial opa1, apoptosis, and heart failure. Cardiovasc Res 84(1):91–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen L et al (2012) Opa1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and MTDNA instability. J Am Heart Assoc 1(5):e003012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Piquereau J et al (2012) Down-regulation of opa1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload. Cardiovasc Res 94(3):408–417

    Article  CAS  PubMed  Google Scholar 

  65. Chen Y, Liu YQ, Dorn GW (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109(12):1327–1U36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fang L et al (2007) Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo. Life Sci 80(23):2154–2160

    Article  CAS  PubMed  Google Scholar 

  67. Yu HY et al (2011) Mitofusin 2 inhibits angiotensin II-induced myocardial hypertrophy. J Cardiovasc Pharmacol Ther 16(2):205–211

    Article  CAS  PubMed  Google Scholar 

  68. Lopaschuk GD et al (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258

    Article  CAS  PubMed  Google Scholar 

  69. Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85(3):1093–1129

    Article  CAS  PubMed  Google Scholar 

  70. Maarman G et al (2013) A comprehensive review: the evolution of animal models in pulmonary hypertension research; are we there yet? Pulm Circ 3(4):739–756

    Article  PubMed  PubMed Central  Google Scholar 

  71. Piao L et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88(1):47–60

    Article  CAS  PubMed  Google Scholar 

  72. Lundgrin EL et al (2013) Fasting 2-deoxy-2-[18f]fluoro-d-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc 10(1):1–9

    Article  PubMed  PubMed Central  Google Scholar 

  73. Marsboom G et al (2012) Lung (18)f-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185(6):670–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Oikawa M et al (2005) Increased [18f]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J Am Coll Cardiol 45(11):1849–1855

    Article  CAS  PubMed  Google Scholar 

  75. Daicho T et al (2009) Possible involvement of mitochondrial energy-producing ability in the development of right ventricular failure in monocrotaline-induced pulmonary hypertensive rats. J Pharmacol Sci 111(1):33–43

    Article  CAS  PubMed  Google Scholar 

  76. Vonk Noordegraaf A, Galie N (2011) The role of the right ventricle in pulmonary arterial hypertension. Eur Respir Rev 20(122):243–253

    Article  CAS  PubMed  Google Scholar 

  77. Marsboom G et al (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110(11):1484–1497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ryan J et al (2015) Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med 93(3):229–242

    Article  CAS  PubMed  Google Scholar 

  79. Ryan JJ, Archer SL (2015) Emerging concepts in the molecular basis of pulmonary arterial hypertension part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation 131(19):1691–1702

    Article  PubMed  PubMed Central  Google Scholar 

  80. Sharma H, Ladner AO, Dhillon NK (2017) Mitochondrial dynamics and HIV/opioids mediated pulmonary endothelial dysfunction: implications in HIV-related pulmonary arterial hypertension. Am J Respir Crit Care Med 195

    Google Scholar 

  81. Schwall CT, Greenwood VL, Alder NN (2012) The stability and activity of respiratory complex II is cardiolipin-dependent. Biochim Biophys Acta, Bioenerg 1817(9):1588–1596

    Article  CAS  Google Scholar 

  82. Tang Z et al (2002) Heart and breast muscle mitochondrial dysfunction in pulmonary hypertension syndrome in broilers (Gallus domesticus). Comp Biochem Physiol A Mol Integr Physiol 132(3):527–540

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

I would like to thank the National Research Foundation of South Africa and the Hatter Institute for Cardiovascular Research in Africa (HICRA), for their continued support. Special thanks for Prof. Sajal Chakraborti for the invitation to contribute a chapter to this highly important book series.

Conflict of Interest

The author has no conflict of interest to declare.

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Authors and Affiliations

  1. Hatter Institute for Cardiovascular Research in Africa (HICRA) and MRC Inter-University, Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Gerald J. Maarman

  2. Cardiovascular Research Group, Division of Medical Physiology, Department of Biomedical Sciences, Stellenbosch University, Tygerberg, South Africa

    Gerald J. Maarman

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  1. Gerald J. Maarman
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Correspondence to Gerald J. Maarman .

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Editors and Affiliations

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

    Sajal Chakraborti

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

    Naranjan S Dhalla

  3. Translational Health Science and Technology (THSTI), Department of Biotechnology, Faridabad, India

    Nirmal K Ganguly

  4. Translational Health Science and Technology (THSTI), Department of Biotechnology, Faridabad, India

    Madhu Dikshit

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Maarman, G.J. (2019). Pulmonary Hypertension and the Right Ventricle: The Roles of Mitochondrial Reactive Oxygen Species in Causing Further Right Ventricular Mitochondrial Changes. In: Chakraborti, S., Dhalla, N., Ganguly, N., Dikshit, M. (eds) Oxidative Stress in Heart Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-13-8273-4_24

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