Skip to main content
SpringerLink
Log in

Mitochondrial and Metabolic Drivers of Pulmonary Vascular Endothelial Dysfunction in Pulmonary Hypertension

  • 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

Pulmonary hypertension (PH) is a deadly and increasingly prevalent vascular disease characterized by excessive pulmonary vascular remodeling and right ventricular dysfunction which leads to right heart failure, multiorgan dysfunction, and premature death. The cause of the vascular remodeling in PH remains elusive, and thus current treatments are marginally effective and prognosis of PH remains poor. Increasing evidence indicates the pathogenic importance of endothelial dysfunction in PH. However, the underlying mechanisms of such dysfunction are not well described. Endothelial apoptosis and hyperproliferation have been identified in patients with PH. Both are linked with the increased oxidative stress and inflammatory responses, and are influenced by various genetic and exogenous stresses. Importantly, contrary to historic dogma that suggested a negligible role for mitochondria and energy balance in endothelial pathology, recent findings have implicated the role of endothelial metabolism directly in PH. This chapter addresses the emerging role of mitochondria in pulmonary vascular endothelial dysfunction in PH. A more sophisticated understanding of the biochemical, metabolic, molecular, and physiologic underpinnings of this emerging paradigm should enable the development of a new generation of targeted therapies that will stunt or reverse pulmonary vascular remodeling.

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. Potente, M., Gerhardt, H., & Carmeliet, P. (2011). Basic and therapeutic aspects of angiogenesis. Cell, 146(6), 873–887.

    Article  CAS  PubMed  Google Scholar 

  2. Schermuly, R. T., et al. (2011). Mechanisms of disease: Pulmonary arterial hypertension. Nature Reviews. Cardiology, 8(8), 443–455.

    Article  CAS  PubMed  Google Scholar 

  3. Simonneau, G., et al. (2013). Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology, 62(25 Suppl), D34–D41.

    Article  PubMed  Google Scholar 

  4. Lee, R., Channon, K. M., & Antoniades, C. (2012). Therapeutic strategies targeting endothelial function in humans: Clinical implications. Current Vascular Pharmacology, 10(1), 77–93.

    Article  CAS  PubMed  Google Scholar 

  5. Michelakis, E. D. (2006). Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: Heterogeneous BMP signaling may have therapeutic implications. Circulation Research, 98(2), 172–175.

    Article  CAS  PubMed  Google Scholar 

  6. Davidson, S. M., & Duchen, M. R. (2007). Endothelial mitochondria: Contributing to vascular function and disease. Circulation Research, 100(8), 1128–1141.

    Article  CAS  PubMed  Google Scholar 

  7. Dromparis, P., & Michelakis, E. D. (2013). Mitochondria in vascular health and disease. Annual Review of Physiology, 75, 95–126.

    Article  CAS  PubMed  Google Scholar 

  8. Kluge, M. A., Fetterman, J. L., & Vita, J. A. (2013). Mitochondria and endothelial function. Circulation Research, 112(8), 1171–1188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Culic, O., Gruwel, M. L., & Schrader, J. (1997). Energy turnover of vascular endothelial cells. The American Journal of Physiology, 273(1 Pt 1), C205–C213.

    CAS  PubMed  Google Scholar 

  10. Dranka, B. P., Hill, B. G., & Darley-Usmar, V. M. (2010). Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free Radical Biology & Medicine, 48(7), 905–914.

    Article  CAS  Google Scholar 

  11. Quintero, M., et al. (2006). Mitochondria as signaling organelles in the vascular endothelium. Proceedings of the National Academy of Sciences of the United States of America, 103(14), 5379–5384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sakao, S., et al. (2005). Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB Journal, 19(9), 1178–1180.

    CAS  PubMed  Google Scholar 

  13. Xu, W., & Erzurum, S. C. (2011). Endothelial cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension. Comprehensive Physiology, 1(1), 357–372.

    PubMed  Google Scholar 

  14. Warburg, O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314.

    Article  CAS  PubMed  Google Scholar 

  15. Wang, T., Marquardt, C., & Foker, J. (1976). Aerobic glycolysis during lymphocyte proliferation. Nature, 261(5562), 702–705.

    Article  CAS  PubMed  Google Scholar 

  16. Bonnet, S., et al. (2006). An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation, 113(22), 2630–2641.

    Article  CAS  PubMed  Google Scholar 

  17. Iqbal, M., et al. (2001). Lung mitochondrial dysfunction in pulmonary hypertension syndrome. I. Site-specific defects in the electron transport chain. Poultry Science, 80(4), 485–495.

    Article  CAS  PubMed  Google Scholar 

  18. Michelakis, E. D., et al. (2002). Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation, 105(2), 244–250.

    Article  CAS  PubMed  Google Scholar 

  19. Sharma, S., et al. (2008). Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension. American Journal of Physiology. Lung Cellular and Molecular Physiology, 294(1), L46–L56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Garber, K. (2006). Energy deregulation: Licensing tumors to grow. Science, 312(5777), 1158–1159.

    Article  CAS  PubMed  Google Scholar 

  21. Ablikim, M., et al. (2006). Measurements of the continuum R(uds) and R values in e(+)e(−) annihilation in the energy region between 3.650 and 3.872 GeV. Physical Review Letters, 97(26), 262001.

    Article  CAS  PubMed  Google Scholar 

  22. Fijalkowska, I., et al. (2010). Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. The American Journal of Pathology, 176(3), 1130–1138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Parra-Bonilla, G., et al. (2010). Critical role for lactate dehydrogenase a in aerobic glycolysis that sustains pulmonary microvascular endothelial cell proliferation. American Journal of Physiology. Lung Cellular and Molecular Physiology, 299(4), L513–L522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bonnet, S., et al. (2007). The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proceedings of the National Academy of Sciences of the United States of America, 104(27), 11418–11423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Green, D. R., & Reed, J. C. (1998). Mitochondria and apoptosis. Science, 281(5381), 1309–1312.

    Article  CAS  PubMed  Google Scholar 

  26. Loike, J. D., et al. (1992). Hypoxia induces glucose transporter expression in endothelial cells. The American Journal of Physiology, 263(2 Pt 1), C326–C333.

    CAS  PubMed  Google Scholar 

  27. Xu, W., et al. (2007). Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 104(4), 1342–1347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. O’Donnell-Tormey, J., et al. (1987). Secretion of pyruvate. An antioxidant defense of mammalian cells. The Journal of Experimental Medicine, 165(2), 500–514.

    Article  PubMed  Google Scholar 

  29. Humbert, M., et al. (2004). Cellular and molecular pathobiology of pulmonary arterial hypertension. Journal of the American College of Cardiology, 43(12 Suppl S), 13S–24S.

    Article  CAS  PubMed  Google Scholar 

  30. Kim, J., et al. (2013). An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nature Medicine, 19(1), 74–82.

    Article  CAS  PubMed  Google Scholar 

  31. Duong, H. T., et al. (2011). Pulmonary artery endothelium resident endothelial colony-forming cells in pulmonary arterial hypertension. Pulmonary Circulation, 1(4), 475–486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Steiner, M. K., et al. (2009). Interleukin-6 overexpression induces pulmonary hypertension. Circulation Research, 104(2), 236–244. 28p following 244.

    Article  CAS  PubMed  Google Scholar 

  33. Antigny, F., et al. (2016). Potassium channel subfamily K member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation, 133(14), 1371–1385.

    Article  CAS  PubMed  Google Scholar 

  34. Lunt, S. Y., & Vander Heiden, M. G. (2011). Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annual Review of Cell and Developmental Biology, 27, 441–464.

    Article  CAS  PubMed  Google Scholar 

  35. Zhao, Y., Butler, E. B., & Tan, M. (2013). Targeting cellular metabolism to improve cancer therapeutics. Cell Death & Disease, 4, e532.

    Article  CAS  Google Scholar 

  36. Bertero, T., et al. (2016). Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. Journal of Clinical Investigation, 126(9), 3313–3335.

    Article  PubMed  PubMed Central  Google Scholar 

  37. White, K., Loscalzo, J., & Chan, S. Y. (2012). Holding our breath: The emerging and anticipated roles of microRNA in pulmonary hypertension. Pulmonary Circulation, 2(3), 278–290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sutendra, G., & Michelakis, E. D. (2014). The metabolic basis of pulmonary arterial hypertension. Cell Metabolism, 19(4), 558–573.

    Article  CAS  PubMed  Google Scholar 

  39. Diebold, I., et al. (2015). BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metabolism, 21(4), 596–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Spiekerkoetter, E., et al. (2013). FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. The Journal of Clinical Investigation, 123(8), 3600–3613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Guignabert, C., et al., Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.. J Clin Invest, 2016. 126(9):3207–3218.

    Google Scholar 

  42. Paddenberg, R., et al. (2003). Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. American Journal of Physiology. Lung Cellular and Molecular Physiology, 284(5), L710–L719.

    Article  CAS  PubMed  Google Scholar 

  43. Redout, E. M., et al. (2007). Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species. Cardiovascular Research, 75(4), 770–781.

    Article  CAS  PubMed  Google Scholar 

  44. Al-Mehdi, A. B., et al. (2012). Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Science Signaling, 5(231), ra47.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ruchko, M. V., et al. (2011). The DNA glycosylase Ogg1 defends against oxidant-induced mtDNA damage and apoptosis in pulmonary artery endothelial cells. Free Radical Biology & Medicine, 50(9), 1107–1113.

    Article  CAS  Google Scholar 

  46. Sud, N., et al. (2008). Asymmetric dimethylarginine inhibits HSP90 activity in pulmonary arterial endothelial cells: Role of mitochondrial dysfunction. American Journal of Physiology. Cell Physiology, 294(6), C1407–C1418.

    Article  CAS  PubMed  Google Scholar 

  47. Dhanasekaran, A., et al. (2004). Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. The Journal of Biological Chemistry, 279(36), 37575–37587.

    Article  CAS  PubMed  Google Scholar 

  48. Herget, J., et al. (2000). A possible role of the oxidant tissue injury in the development of hypoxic pulmonary hypertension. Physiological Research, 49(5), 493–501.

    CAS  PubMed  Google Scholar 

  49. Lakshminrusimha, S., et al. (2006). Superoxide dismutase improves oxygenation and reduces oxidation in neonatal pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 174(12), 1370–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoshikawa, Y., et al. (2001). Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. Journal of Applied Physiology (1985), 90(4), 1299–1306.

    CAS  Google Scholar 

  51. McMurtry, M. S., et al. (2004). Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circulation Research, 95(8), 830–840.

    Article  CAS  PubMed  Google Scholar 

  52. Paky, A., et al. (1993). Endogenous production of superoxide by rabbit lungs: Effects of hypoxia or metabolic inhibitors. Journal of Applied Physiology (1985), 74(6), 2868–2874.

    CAS  Google Scholar 

  53. Archer, S. L., et al. (1993). A redox-based O2 sensor in rat pulmonary vasculature. Circulation Research, 73(6), 1100–1112.

    Article  CAS  PubMed  Google Scholar 

  54. Lawrie, A. M., et al. (1996). A role for calcium influx in the regulation of mitochondrial calcium in endothelial cells. The Journal of Biological Chemistry, 271(18), 10753–10759.

    Article  CAS  PubMed  Google Scholar 

  55. Marchi, S., & Pinton, P. (2014). The mitochondrial calcium uniporter complex: Molecular components, structure and physiopathological implications. The Journal of Physiology, 592(Pt 5), 829–839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sutendra, G., et al. (2011). The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Science Translational Medicine, 3(88), 88ra55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rizzuto, R., et al. (2012). Mitochondria as sensors and regulators of calcium signalling. Nature Reviews. Molecular Cell Biology, 13(9), 566–578.

    Article  CAS  PubMed  Google Scholar 

  58. Dedkova, E. N., et al. (2004). Mitochondrial calcium uptake stimulates nitric oxide production in mitochondria of bovine vascular endothelial cells. American Journal of Physiology. Cell Physiology, 286(2), C406–C415.

    Article  CAS  PubMed  Google Scholar 

  59. Rouault, T. A., & Tong, W. H. (2008). Iron-sulfur cluster biogenesis and human disease. Trends in Genetics, 24(8), 398–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Semenza, G. L. (2007). Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. The Biochemical Journal, 405(1), 1–9.

    Article  CAS  PubMed  Google Scholar 

  61. Rouault, T. A. (2012). Biogenesis of iron-sulfur clusters in mammalian cells: New insights and relevance to human disease. Disease Models & Mechanisms, 5(2), 155–164.

    Article  CAS  Google Scholar 

  62. Cameron, J. M., et al. (2011). Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. American Journal of Human Genetics, 89(4), 486–495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Navarro-Sastre, A., et al. (2011). A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. American Journal of Human Genetics, 89(5), 656–667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chan, S. Y., et al. (2009). MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism, 10(4), 273–284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. White, K., et al. (2015). Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Molecular Medicine, 7(6), 695–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 324(5930), 1029–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Paulin, R., & Michelakis, E. D. (2014). The metabolic theory of pulmonary arterial hypertension. Circulation Research, 115(1), 148–164.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Ms. Diane Margaria for expert administrative assistance. This work was supported by the NIH (grants HL096834, HL124021) and the American Heart Association (S.Y.C.).

Author information

Authors and Affiliations

  1. Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, 200 Lothrop Street BST1704.2, Pittsburgh, PA, 15261, USA

    Qiujun Yu & Stephen Y. Chan M.D., Ph.D.

  2. Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, 200 Lothrop Street BST1704.2, Pittsburgh, PA, 15261, USA

    Qiujun Yu & Stephen Y. Chan M.D., Ph.D.

Authors
  1. Qiujun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen Y. Chan M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen Y. Chan M.D., Ph.D. .

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

Yu, Q., Chan, S.Y. (2017). Mitochondrial and Metabolic Drivers of Pulmonary Vascular Endothelial Dysfunction in Pulmonary Hypertension. 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_24

Download citation

Publish with us

Policies and ethics

Search

Navigation