Skip to main content
SpringerLink
Log in
Book cover

Targeting Cellular Signalling Pathways in Lung Diseases pp 435–445Cite as

Potential Cellular Targets Associated with the Signaling of the Pulmonary Hypertension

  • Chapter
  • First Online:

  • 918 Accesses

Abstract

The mean value of normal pulmonary arterial pressure in human beings is 12–16 mmHg. Pulmonary arterial pressure beyond 25 mmHg is associated with the condition of pulmonary hypertension, and is related to right heart failure. It has been noticed that the pathophysiology of pulmonary hypertension is a multifactor process that involves both structural and functional changes in the pulmonary vasculature and is responsible for the increase in the pulmonary vascular resistance. There are several factors which are associated with the alterations in pulmonary pressure and release from the vascular endothelium such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factors. Disturbances in these factors lead to pulmonary hypertension. There are several important potential cellular targets which are associated with the pulmonary hypertension signaling such as TGF-β, BMR2, Rho, ROCK, CypA, Bsg, and AMPK. This chapter review all these potential cellular targets.

This is a preview of subscription content, 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   149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
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

Learn about institutional subscriptions

References

  1. Hoeper MM, Ghofrani HA, Grünig E, Klose H, Olschewski H, Rosenkranz S (2017) Pulmonary hypertension. Dtsch Arztebl Int 114(5):73

    PubMed  Google Scholar 

  2. Thenappan T, Chan SY, Weir EK (2018) Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am J Phys Heart Circ Phys 315(5):H1322–H1331

    CAS  Google Scholar 

  3. Prins KW, Thenappan T (2016) WHO Group I pulmonary hypertension: epidemiology and pathophysiology. Cardiol Clin 34(3):363

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F (2011) Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol 8(8):443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 53:1

    Article  CAS  Google Scholar 

  6. Buckley MS, Staib RL, Wicks LM (2013) Combination therapy in the management of pulmonary arterial hypertension. Int J Clin Pract 67:13–23

    Article  Google Scholar 

  7. Ichida F, Uese KI, Hamamichi Y, Hashimoto I, Tsubata SI, Fukahara K, Murakami A, Miyawaki T (1998) Chronic effects of oral prostacyclin analogue on thromboxane a and prostacyclin metabolites in pulmonary hypertension. Pediatr Int 40(1):14–19

    Article  CAS  Google Scholar 

  8. Ghofrani HA, Osterloh IH, Grimminger F (2006) Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5(8):689–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351(16):1655–1665

    Article  CAS  PubMed  Google Scholar 

  10. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115(1):165–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Soon EH (2010) Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122(9):920r927

    Article  CAS  Google Scholar 

  12. Chaouat A, Savale L, Chouaid C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset B, Brandt C, Le Corvoisier P, Weitzenblum E (2009) Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 136(3):678–687

    Article  CAS  PubMed  Google Scholar 

  13. Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S (2009) Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 10(1):6

    Article  PubMed  PubMed Central  Google Scholar 

  14. Moudgil R, Michelakis ED, Archer SL (2006) The role of K+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13(8):615–632

    Article  CAS  PubMed  Google Scholar 

  15. Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JXJ (2004) Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci 101(38):13861–13866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M (2000) Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6(6):698–702

    Article  CAS  PubMed  Google Scholar 

  17. Chelladurai P, Seeger W, Pullamsetti SS (2012) Matrix metalloproteinases and their inhibitors in pulmonary hypertension. Eur Respir J 40(3):766–782

    Google Scholar 

  18. Sacks RS, Remillard CV, Agange N, Auger WR, Thistlethwaite PA, Yuan JXJ (2006) Molecular biology of chronic thromboembolic pulmonary hypertension. Semin Thorac Cardiovasc Surg 18(3):265–276

    Article  PubMed  Google Scholar 

  19. Alias S, Redwan B, Panzenböck A, Winter MP, Schubert U, Voswinckel R, Frey MK, Jakowitsch J, Alimohammadi A, Hobohm L, Mangold A (2014) Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension. Arterioscler Thromb Vasc Biol 34(4):810–819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jeffery TK, Morrell NW (2002) Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 45(3):173–202

    Article  CAS  PubMed  Google Scholar 

  21. Gajecki D, Gawrys J, Szahidewicz-Krupska E and Doroszko A (2020) Novel Molecular Mechanisms of Pulmonary Hypertension: A Search for Biomarkers and Novel Drug Targets—From Bench to Bed Site. Oxidative Medicine and Cellular Longevity, 2020

    Google Scholar 

  22. Maron BA, Leopold JA (2015) Emerging concepts in the molecular basis of pulmonary arterial hypertension: part II: neurohormonal signaling contributes to the pulmonary vascular and right ventricular pathophenotype of pulmonary arterial hypertension. Circulation 131(23):2079–2091

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lai YC, Potoka KC, Champion HC, Mora AL, Gladwin MT (2014) Pulmonary arterial hypertension: the clinical syndrome. Circ Res 115(1):115–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thompson AR, Lawrie A (2017) Targeting vascular remodeling to treat pulmonary arterial hypertension. Trends Mol Med 23(1):31–45

    Article  CAS  PubMed  Google Scholar 

  25. Montani D, Günther S, Dorfmüller P, Perros F, Girerd B, Garcia G, Jaïs X, Savale L, Artaud-Macari E, Price LC, Humbert M (2013) Pulmonary arterial hypertension. Orphanet J Rare Dis 8(1):97

    Article  PubMed  PubMed Central  Google Scholar 

  26. Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA III, Palomero T, Sumazin P, Kim HR, Talati MH, West J (2012) Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 5(3):336–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, Chelghoum N, Coulet F, Bonnet D, Dorfmüller P, Fadel E (2014) EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 46(1):65–69

    Article  CAS  PubMed  Google Scholar 

  28. Julian L, Olson MF (2014) Rho-associated coiled-coil containing kinases (ROCK) structure, regulation, and functions. Small GTPases 5(2):e29846

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yaoita N, Satoh K, Satoh T, Sugimura K, Tatebe S, Yamamoto S, Aoki T, Miura M, Miyata S, Kawamura T, Horiuchi H (2016) Thrombin-activatable fibrinolysis inhibitor in chronic thromboembolic pulmonary hypertension. Arterioscler Thromb Vasc Biol 36(6):1293–1301

    Article  CAS  PubMed  Google Scholar 

  30. Amano M, Nakayama M, Kaibuchi K (2010) Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity. Cytoskeleton 67(9):545–554

    Article  CAS  PubMed  Google Scholar 

  31. Wang XY, Mo D, Tian W, Liu XX, Zhou YG, Sun Y, Feng YD, Xiao X, Hao XW, Zhang HN, Li C (2019) Inhibition of RhoA/ROCK signaling pathway ameliorates hypoxic pulmonary hypertension via HIF-1α-dependent functional TRPC channels. Toxicol Appl Pharmacol 369:60–72

    Article  CAS  PubMed  Google Scholar 

  32. Wei H, Zhang D, Liu L, Xia W, Li F (2019) Rho signaling pathway enhances proliferation of PASMCs by suppressing nuclear translocation of Smad1 in PAH. Exp Ther Med 17(1):71–78

    CAS  PubMed  Google Scholar 

  33. Yang G, Caldwell RB, Yao L, Romero MJ, Toque HA, Caldwell RW (2010) The role of RhoA/rho kinase pathway in endothelial dysfunction. J Cardiovasc Dis Res 1(4):165–170

    Article  PubMed  PubMed Central  Google Scholar 

  34. Antoniu SA (2012) Targeting RhoA/ROCK pathway in pulmonary arterial hypertension. Expert Opin Ther Targets 16(4):355–363

    Article  CAS  PubMed  Google Scholar 

  35. Xue C, Sowden M, Berk BC (2017) Extracellular cyclophilin a, especially acetylated, causes pulmonary hypertension by stimulating endothelial apoptosis, redox stress, and inflammation. Arterioscler Thromb Vasc Biol 37(6):1138–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Satoh K (2015) Cyclophilin a in cardiovascular homeostasis and diseases. Tohoku J Exp Med 235(1):1–15

    Article  CAS  PubMed  Google Scholar 

  37. Miller LH, Ackerman HC, Su XZ, Wellems TE (2013) Malaria biology and disease pathogenesis: insights for new treatments. Nat Med 19(2):156–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Satoh K, Satoh T, Kikuchi N, Omura J, Kurosawa R, Suzuki K, Sugimura K, Aoki T, Nochioka K, Tatebe S, Miyamichi-Yamamoto S (2014) Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res 115(8):738–750

    Article  CAS  PubMed  Google Scholar 

  39. Sunamura S, Satoh K, Kurosawa R, Ohtsuki T, Kikuchi N, Elias-Al-Mamun M, Shimizu T, Ikeda S, Suzuki K, Satoh T, Omura J (2018) Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice. Proc Natl Acad Sci 115(30):E7129–E7138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Satoh K, Kikuchi N, Satoh T, Kurosawa R, Sunamura S, Siddique MAH, Omura J, Yaoita N, Shimokawa H (2018) Identification of novel therapeutic targets for pulmonary arterial hypertension. Int J Mol Sci 19(12):4081

    Article  PubMed Central  Google Scholar 

  41. Satoh K, Nigro P, Berk BC (2010) Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin a. Antioxid Redox Signal 12(5):675–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fisslthaler B, Fleming I (2009) Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res 105(2):114–127

    Article  CAS  PubMed  Google Scholar 

  43. Noda K, Nakajima S, Godo S, Saito H, Ikeda S, Shimizu T, Enkhjargal B, Fukumoto Y, Tsukita S, Yamada T, Katagiri H (2014) Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice. PLoS One 9(11):e110446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Nagata D, Kiyosue A, Takahashi M, Satonaka H, Tanaka K, Sata M, Nagano T, Nagai R, Hirata Y (2009) A new constitutively active mutant of AMP-activated protein kinase inhibits anoxia-induced apoptosis of vascular endothelial cell. Hypertens Res 32(2):133–139

    Article  CAS  PubMed  Google Scholar 

  45. Igata M, Motoshima H, Tsuruzoe K, Kojima K, Matsumura T, Kondo T, Taguchi T, Nakamaru K, Yano M, Kukidome D, Matsumoto K (2005) Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ Res 97(8):837–844

    Article  CAS  PubMed  Google Scholar 

  46. Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Otsuki T, Kozu K, Numano K, Suzuki K, Sunamura S (2016) Protective roles of endothelial AMP-activated protein kinase against hypoxia-induced pulmonary hypertension in mice. Circ Res 119(2):197–209

    Article  CAS  PubMed  Google Scholar 

  47. Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, Karibe A, Kagaya Y, Ishii N, Sugamura K, Shimokawa H (2009) Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res 81(1):226–234

    Article  CAS  PubMed  Google Scholar 

  48. Rafikova O, Meadows ML, Kinchen JM, Mohney RP, Maltepe E, Desai AA, Yuan JXJ, Garcia JG, Fineman JR, Rafikov R, Black SM (2016) Metabolic changes precede the development of pulmonary hypertension in the monocrotaline exposed rat lung. PLoS One 11(3):e0150480

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Chen C, Luo F, Wu P, Huang Y, Das A, Chen S, Chen J, Hu X, Li F, Fang Z, Zhou S (2020) Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China. J Cell Mol Med 24(4):2484–2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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 

  51. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM (2010) Hypoxia inducible-factor1α regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 176(3):1130–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Qin L, D’Alessandro-Gabazza CN, Aoki S, Gil-Bernabe P, Yano Y, Takagi T, Boveda-Ruiz D, Ramirez Marmol AY, San Martin Montenegro VT, Toda M, Miyake Y (2010) Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 8(4):808–816

    Article  CAS  PubMed  Google Scholar 

  53. Antovic JP, Blombäck M (2002) Thrombin-activatable fibrinolysis inhibitor antigen and TAFI activity in patients with APC resistance caused by factor V Leiden mutation. Thromb Res 106(1):59–62

    Article  CAS  PubMed  Google Scholar 

  54. Miljić P, Heylen E, Willemse J, Đorđević V, Radojković D, Čolović M, Elezović I, Hendriks D (2010) Thrombin activatable fibrinolysis inhibitor (TAFI): a molecular link between coagulation and fibrinolysis. Srp Arh Celok Lek 138(suppl. 1):74–78

    Article  PubMed  Google Scholar 

  55. Bouma BN, Meijers JCM (2003) Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). J Thromb Haemost 1(7):1566–1574

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmacology and Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh, India

    Meemansha Sharma, Thakur Uttam Singh, Madhu Cholanhalli Lingaraju & Subhashree Parida

Authors
  1. Meemansha Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thakur Uttam Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Madhu Cholanhalli Lingaraju
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Subhashree Parida
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Kamal Dua

  2. Drug Development and Innovation Centre, University of Alberta, Edmonton, AB, Canada

    Raimar Löbenberg

  3. Haematology and Hemotherapy Center, State University of Campinas, Campinas, São Paulo, Brazil

    Ângela Cristina Malheiros Luzo

  4. Graduate School of Health, Discipline of Pharmacy, University of Technology Sydney, Sydney, NSW, Australia

    Shakti Shukla

  5. School of Pharmaceutical Sciences & Division of Research & Development, Lovely Professional University, Phagwara, Punjab, India

    Saurabh Satija

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sharma, M., Singh, T.U., Lingaraju, M.C., Parida, S. (2021). Potential Cellular Targets Associated with the Signaling of the Pulmonary Hypertension. In: Dua, K., Löbenberg, R., Malheiros Luzo, Â.C., Shukla, S., Satija, S. (eds) Targeting Cellular Signalling Pathways in Lung Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-33-6827-9_19

Download citation

Publish with us

Policies and ethics

Search

Navigation