Skip to main content
SpringerLink
Log in

Targeting Molecular and Cellular Mechanisms of Pulmonary Arterial Hypertension

  • Chapter
  • First Online:
Targeting Cellular Signalling Pathways in Lung Diseases

  • 963 Accesses

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease of the pulmonary circulation, characterized by pulmonary vascular remodeling leading to elevated pulmonary arterial pressure, increased pulmonary vascular resistance, and right heart failure. Unfortunately, up until now, no definite cure exists for this disease. Currently available drugs focus on pulmonary vasodilation, anti-proliferation, and augmentation of endothelial function by targeting nitric oxide, endothelin, voltage-gated calcium channels, and prostacyclin signaling pathways. However, these drugs only partially improve survival and quality of life as they do not address the underlying pulmonary vascular remodeling. Over the past few years, attempts have been made to identify effective therapies that target different, anti-remodeling mechanisms and signaling pathways. Targets for these therapies include genetic and epigenetic modifications, growth factors and proliferation, inflammation and immunomodulation, endothelial-mesenchymal transition, and metabolic abnormalities. In this chapter, we outline and discuss promising novel therapeutic approaches that target diverse molecular and cellular signaling mechanisms involved in PAH.

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 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

Institutional subscriptions

References

  1. Benza RL et al (2012) An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 142(2):448–456

    Article  PubMed  Google Scholar 

  2. Peacock AJ et al (2007) An epidemiological study of pulmonary arterial hypertension. Eur Respir J 30(1):104–109

    Article  CAS  PubMed  Google Scholar 

  3. Humbert M et al (2019) Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J 53(1)

    Google Scholar 

  4. Southgate L et al (2020) Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol 17(2):85–95

    Article  CAS  PubMed  Google Scholar 

  5. Machado RD et al (2015) Pulmonary arterial hypertension: a current perspective on established and emerging molecular genetic defects. Hum Mutat 36(12):1113–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Andruska A, Spiekerkoetter E (2018) Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: contributions to pulmonary arterial hypertension. Int J Mol Sci 19(9)

    Google Scholar 

  7. Atkinson C et al (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105(14):1672–1678

    Article  CAS  PubMed  Google Scholar 

  8. Chen NY et al (2016) Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 311(2):L238–L254

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hong KH et al (2008) Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation 118(7):722–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. West J et al (2004) Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94(8):1109–1114

    Article  CAS  PubMed  Google Scholar 

  11. West J et al (2008) Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295(5):L744–L755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Reynolds AM et al (2012) Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J 39(2):329–343

    Article  CAS  PubMed  Google Scholar 

  13. Reynolds AM et al (2007) Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 292(5):L1182–L1192

    Article  CAS  PubMed  Google Scholar 

  14. Harper RL et al (2016) BMPR2 gene therapy for PAH acts via Smad and non-Smad signalling. Respirology 21(4):727–733

    Article  PubMed  Google Scholar 

  15. Dunmore BJ et al (2020) 4PBA restores signalling of a cysteine-substituted mutant BMPR2 receptor found in patients with PAH. Am J Respir Cell Mol Biol 63(2):160–171

    Article  CAS  PubMed  Google Scholar 

  16. Drake KM et al (2013) Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 49(3):403–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Klionsky DJ et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12(1):1–222

    Article  PubMed  PubMed Central  Google Scholar 

  18. Savai R et al (2014) Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension. Nat Med 20(11):1289–1300

    Article  CAS  PubMed  Google Scholar 

  19. Botros L et al (2020) The effects of mercaptopurine on pulmonary vascular resistance and BMPR2 expression in pulmonary arterial hypertension. Am J Respir Crit Care Med 202(2):296–299

    Article  CAS  PubMed  Google Scholar 

  20. Kurakula K et al (2019) Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling. Eur Respir J 54(3)

    Google Scholar 

  21. Dannewitz Prosseda S et al (2019) FHIT, a novel modifier gene in pulmonary arterial hypertension. Am J Respir Crit Care Med 199(1):83–98

    Article  PubMed  PubMed Central  Google Scholar 

  22. Spiekerkoetter E et al (2013) FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 123(8):3600–3613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yung LM et al (2016) A selective transforming growth factor-beta ligand trap attenuates pulmonary hypertension. Am J Respir Crit Care Med 194(9):1140–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Long L et al (2015) Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 21(7):777–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Spiekerkoetter E et al (2015) Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med 192(2):254–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Spiekerkoetter E et al (2017) Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J 50(3)

    Google Scholar 

  27. Botney MD, Bahadori L, Gold LI (1994) Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta. Am J Pathol 144(2):286–295

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zaiman AL et al (2008) Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med 177(8):896–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen YF et al (2006) Dominant negative mutation of the TGF-beta receptor blocks hypoxia-induced pulmonary vascular remodeling. J Appl Physiol (1985) 100(2):564–571

    Article  CAS  Google Scholar 

  30. Sheares KK et al (2004) Differential effects of TGF-beta1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 287(5):L919–L927

    Article  CAS  PubMed  Google Scholar 

  31. Tielemans B et al (2019) TGFbeta and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension. Drug Discov Today 24(3):703–716

    Article  CAS  PubMed  Google Scholar 

  32. ATS 2020 virtual: PULSAR phase 2 trial results of sotatercept in PAH. ATS 2020 Virtual, June 24, 2020

    Google Scholar 

  33. Archer SL et al (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121(24):2661–2671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Napoli C, Benincasa G, Loscalzo J (2019) Epigenetic inheritance underlying pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 39(4):653–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu D et al (2017) Hypermethylation of BMPR2 promoter occurs in patients with heritable pulmonary arterial hypertension and inhibits BMPR2 expression. Am J Respir Crit Care Med 196(7):925–928

    Article  CAS  PubMed  Google Scholar 

  36. Chelladurai P, Seeger W, Pullamsetti SS (2016) Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives. Eur Respir Rev 25(140):135–140

    Article  PubMed  Google Scholar 

  37. Cavasin MA et al (2012) Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ Res 110(5):739–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhao L et al (2012) Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation 126(4):455–467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lan B et al (2015) Therapeutic efficacy of valproic acid in a combined monocrotaline and chronic hypoxia rat model of severe pulmonary hypertension. PLoS One 10(1):e0117211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Cho YK et al (2010) Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats. Circ J 74(4):760–770

    Article  CAS  PubMed  Google Scholar 

  41. Kim J et al (2015) Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation 131(2):190–199

    Article  PubMed  Google Scholar 

  42. Boucherat O et al (2017) HDAC6: a novel histone deacetylase implicated in pulmonary arterial hypertension. Sci Rep 7(1):4546

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Zurlo G et al (2018) Sirtuin 1 regulates pulmonary artery smooth muscle cell proliferation: role in pulmonary arterial hypertension. J Hypertens 36(5):1164–1177

    Article  CAS  PubMed  Google Scholar 

  44. Yu L et al (2017) Resveratrol protects against pulmonary arterial hypertension in rats via activation of silent information regulator 1. Cell Physiol Biochem 42(1):55–67

    Article  CAS  PubMed  Google Scholar 

  45. Meloche J et al (2015) Bromodomain-containing protein 4: the epigenetic origin of pulmonary arterial hypertension. Circ Res 117(6):525–535

    Article  CAS  PubMed  Google Scholar 

  46. Van der Feen DE et al (2019) Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med 200(7):910–920

    Article  PubMed  Google Scholar 

  47. Meloche J et al (2014) Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 129(7):786–797

    Article  CAS  PubMed  Google Scholar 

  48. Chun HJ, Bonnet S, Chan SY (2017) Translational advances in the field of pulmonary hypertension. translating microRNA biology in pulmonary hypertension. It will take more than “miR” words. Am J Respir Crit Care Med 195(2):167–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhou G, Chen T, Raj JU (2015) MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 52(2):139–151

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mondejar-Parreno G et al (2019) miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries. J Physiol 597(4):1185–1197

    Article  CAS  PubMed  Google Scholar 

  51. Mondejar-Parreno G et al (2019) miR-1 induces endothelial dysfunction in rat pulmonary arteries. J Physiol Biochem 75(4):519–529

    Article  CAS  PubMed  Google Scholar 

  52. Sysol JR et al (2018) Micro-RNA-1 is decreased by hypoxia and contributes to the development of pulmonary vascular remodeling via regulation of sphingosine kinase 1. Am J Physiol Lung Cell Mol Physiol 314(3):L461–L472

    Article  PubMed  CAS  Google Scholar 

  53. Connolly M et al (2020) miR-1-5p targets TGF-betaR1 and is suppressed in the hypertrophying hearts of rats with pulmonary arterial hypertension. PLoS One 15(2):e0229409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yue Y et al (2018) miR-143 and miR-145 promote hypoxia-induced proliferation and migration of pulmonary arterial smooth muscle cells through regulating ABCA1 expression. Cardiovasc Pathol 37:15–25

    Article  CAS  PubMed  Google Scholar 

  55. Caruso P et al (2017) Identification of microRNA-124 as a major regulator of enhanced endothelial cell glycolysis in pulmonary arterial hypertension via PTBP1 (polypyrimidine tract binding protein) and pyruvate kinase M2. Circulation 136(25):2451–2467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang H et al (2017) Metabolic and proliferative state of vascular adventitial fibroblasts in pulmonary hypertension is regulated through a microRNA-124/PTBP1 (polypyrimidine tract binding protein 1)/pyruvate kinase muscle axis. Circulation 136(25):2468–2485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang D et al (2014) MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts. Circ Res 114(1):67–78

    Article  CAS  PubMed  Google Scholar 

  58. Kang K et al (2013) MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem 288(35):25414–25427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen J et al (2018) Effect of miR-29b on the proliferation and apoptosis of pulmonary artery smooth muscle cells by targeting Mcl-1 and CCND2. Biomed Res Int 2018:6051407

    PubMed  PubMed Central  Google Scholar 

  60. Liu T et al (2019) Down-regulation of miR-204 attenuates endothelial-mesenchymal transition by enhancing autophagy in hypoxia-induced pulmonary hypertension. Eur J Pharmacol 863:172673

    Article  CAS  PubMed  Google Scholar 

  61. Meloche J et al (2015) miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol 309(6):C363–C372

    Article  CAS  PubMed  Google Scholar 

  62. Liu A et al (2019) Role of miR-223-3p in pulmonary arterial hypertension via targeting ITGB3 in the ECM pathway. Cell Prolif 52(2):e12550

    Article  PubMed  CAS  Google Scholar 

  63. Zeng Y et al (2016) MicroRNA-223 attenuates hypoxia-induced vascular remodeling by targeting RhoB/MLC2 in pulmonary arterial smooth muscle cells. Sci Rep 6:24900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhao H et al (2020) miR-181b-5p inhibits endothelial-mesenchymal transition in monocrotaline-induced pulmonary arterial hypertension by targeting endocan and TGFBR1. Toxicol Appl Pharmacol 386:114827

    Article  PubMed  CAS  Google Scholar 

  65. Zhao H et al (2020) miR-181a/b-5p ameliorates inflammatory response in monocrotaline-induced pulmonary arterial hypertension by targeting endocan. J Cell Physiol 235(5):4422–4433

    Article  CAS  PubMed  Google Scholar 

  66. Zeng Z et al (2018) Anti-apoptosis endothelial cell-secreted microRNA-195-5p promotes pulmonary arterial smooth muscle cell proliferation and migration in pulmonary arterial hypertension. J Cell Biochem 119(2):2144–2155

    Article  CAS  PubMed  Google Scholar 

  67. Liu T et al (2019) miR-27a promotes endothelial-mesenchymal transition in hypoxia-induced pulmonary arterial hypertension by suppressing BMP signaling. Life Sci 227:64–73

    Article  CAS  PubMed  Google Scholar 

  68. Zhang W et al (2020) MicroRNA15a5p induces pulmonary artery smooth muscle cell apoptosis in a pulmonary arterial hypertension model via the VEGF/p38/MMP2 signaling pathway. Int J Mol Med 45(2):461–474

    CAS  PubMed  Google Scholar 

  69. Yu RH, Wang LM, Hu XH (2019) MiR-135a inhibitor alleviates pulmonary arterial hypertension through beta-Catenin/GSK-3beta signaling pathway. Eur Rev Med Pharmacol Sci 23(21):9574–9581

    PubMed  Google Scholar 

  70. Lee HW, Park SH (2017) Elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model. Oncotarget 8(22):35609–35618

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lee HW, Park SH (2017) Correction: elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model. Oncotarget 8(35):59999

    Article  PubMed  PubMed Central  Google Scholar 

  72. Cai Z et al (2018) MiR-125a-5p ameliorates monocrotaline-induced pulmonary arterial hypertension by targeting the TGF-beta1 and IL-6/STAT3 signaling pathways. Exp Mol Med 50(4):45

    Article  PubMed Central  CAS  Google Scholar 

  73. Luo L et al (2020) miR-125a-5p inhibits glycolysis by targeting hexokinase-II to improve pulmonary arterial hypertension. Aging (Albany NY) 12(10):9014–9030

    Article  CAS  Google Scholar 

  74. Ma C et al (2017) MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling. J Mol Med (Berl) 95(9):977–993

    Article  CAS  Google Scholar 

  75. Zhu G et al (2018) miR371b5p inhibits endothelial cell apoptosis in monocrotaline-induced pulmonary arterial hypertension via PTEN/PI3K/Akt signaling pathways. Mol Med Rep 18(6):5489–5501

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhou C et al (2019) Mir-455-3p-1 represses FGF7 expression to inhibit pulmonary arterial hypertension through inhibiting the RAS/ERK signaling pathway. J Mol Cell Cardiol 130:23–35

    Article  CAS  PubMed  Google Scholar 

  77. Zhao M et al (2019) MiR-19a modulates hypoxia-mediated cell proliferation and migration via repressing PTEN in human pulmonary arterial smooth muscle. Life Sci 239:116928

    Article  CAS  PubMed  Google Scholar 

  78. Bi R et al (2015) MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor gamma dependent Hsp90-eNOS signaling and nitric oxide production. Biochem Biophys Res Commun 460(2):469–475

    Article  CAS  PubMed  Google Scholar 

  79. Sahoo S et al (2016) MEF2C-MYOCD and leiomodin1 suppression by miRNA-214 promotes smooth muscle cell phenotype switching in pulmonary arterial hypertension. PLoS One 11(5):e0153780

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Sarrion I et al (2015) Role of circulating miRNAs as biomarkers in idiopathic pulmonary arterial hypertension: possible relevance of miR-23a. Oxidative Med Cell Longev 2015:792846

    Article  Google Scholar 

  81. Yan L et al (2017) Effect of miR-23a on anoxia-induced phenotypic transformation of smooth muscle cells of rat pulmonary arteries and regulatory mechanism. Oncol Lett 13(1):89–98

    Article  CAS  PubMed  Google Scholar 

  82. Zhang Y, Peng B, Han Y (2018) MiR-23a regulates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) through targeting BMPR2/Smad1 signaling. Biomed Pharmacother 103:1279–1286

    Article  CAS  PubMed  Google Scholar 

  83. Wang P et al (2016) miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA. Cell Prolif 49(4):484–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ogorodnikova N, Arenz C (2015) MicroRNA-145-targeted drug and its preventive effect on pulmonary arterial hypertension (patent WO2012153135 A1). Expert Opin Ther Pat 25(6):723–727

    Article  CAS  PubMed  Google Scholar 

  85. Caruso P et al (2012) A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res 111(3):290–300

    Article  CAS  PubMed  Google Scholar 

  86. McLendon JM et al (2015) Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension. J Control Release 210:67–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang AP et al (2015) miR-100 suppresses mTOR signaling in hypoxia-induced pulmonary hypertension in rats. Eur J Pharmacol 765:565–573

    Article  CAS  PubMed  Google Scholar 

  88. Li SS et al (2014) MicroRNA-190 regulates hypoxic pulmonary vasoconstriction by targeting a voltage-gated K(+) channel in arterial smooth muscle cells. J Cell Biochem 115(6):1196–1205

    Article  CAS  PubMed  Google Scholar 

  89. Yang S et al (2012) miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 302(6):L521–L529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang J et al (2020) MicroRNA-483 amelioration of experimental pulmonary hypertension. EMBO Mol Med 12(5):e11303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Connolly M et al (2018) miR-322-5p targets IGF-1 and is suppressed in the heart of rats with pulmonary hypertension. FEBS Open Bio 8(3):339–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zeng Y et al (2015) Hypoxia inducible factor-1 mediates expression of miR-322: potential role in proliferation and migration of pulmonary arterial smooth muscle cells. Sci Rep 5:12098

    Article  PubMed  PubMed Central  Google Scholar 

  93. Baptista R et al (2018) MicroRNA-424(322) as a new marker of disease progression in pulmonary arterial hypertension and its role in right ventricular hypertrophy by targeting SMURF1. Cardiovasc Res 114(1):53–64

    Article  CAS  PubMed  Google Scholar 

  94. Deng B et al (2016) MicroRNA-103/107 is involved in hypoxia-induced proliferation of pulmonary arterial smooth muscle cells by targeting HIF-1beta. Life Sci 147:117–124

    Article  CAS  PubMed  Google Scholar 

  95. Miao R et al (2020) MiR-18a-5p contributes to enhanced proliferation and migration of PASMCs via targeting Notch2 in pulmonary arterial hypertension. Life Sci 257:117919

    Article  CAS  PubMed  Google Scholar 

  96. Brock M et al (2014) AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J 35(45):3203–3211

    Article  CAS  PubMed  Google Scholar 

  97. Tan H et al (2019) MicroRNA30a5p promotes proliferation and inhibits apoptosis of human pulmonary artery endothelial cells under hypoxia by targeting YKL40. Mol Med Rep 20(1):236–244

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Le Ribeuz H et al (2020) In vivo miR-138-5p inhibition alleviates monocrotaline-induced pulmonary hypertension and normalizes pulmonary KCNK3 and SLC45A3 expression. Respir Res 21(1):186

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Li S et al (2013) MicroRNA-138 plays a role in hypoxic pulmonary vascular remodelling by targeting Mst1. Biochem J 452(2):281–291

    Article  CAS  PubMed  Google Scholar 

  100. Liu JJ et al (2018) MicroRNA138 promotes proliferation and suppresses mitochondrial depolarization in human pulmonary artery smooth muscle cells through targeting TASK1. Mol Med Rep 17(2):3021–3027

    CAS  PubMed  Google Scholar 

  101. Chen T et al (2016) miR-17/20 controls prolyl hydroxylase 2 (PHD2)/hypoxia-inducible factor 1 (HIF1) to regulate pulmonary artery smooth muscle cell proliferation. J Am Heart Assoc 5(12)

    Google Scholar 

  102. Chen T et al (2018) PAI-1 is a novel component of the miR-17~92 signaling that regulates pulmonary artery smooth muscle cell phenotypes. Am J Physiol Lung Cell Mol Physiol 315(2):L149–L161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chen T et al (2015) Loss of microRNA-17 approximately 92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5. Am J Respir Crit Care Med 191(6):678–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Guo L et al (2012) The microRNA-328 regulates hypoxic pulmonary hypertension by targeting at insulin growth factor 1 receptor and L-type calcium channel-alpha1C. Hypertension 59(5):1006–1013

    Article  CAS  PubMed  Google Scholar 

  105. Zhao M et al (2019) MiR-629 regulates hypoxic pulmonary vascular remodelling by targeting FOXO3 and PERP. J Cell Mol Med 23(8):5165–5175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhao TF et al (2019) MiR-593-5p promotes the development of hypoxic-induced pulmonary hypertension via targeting PLK1. Eur Rev Med Pharmacol Sci 23(8):3495–3502

    PubMed  Google Scholar 

  107. Zhang X et al (2018) Inhibition of miR-361-5p suppressed pulmonary artery smooth muscle cell survival and migration by targeting ABCA1 and inhibiting the JAK2/STAT3 pathway. Exp Cell Res 363(2):255–261

    Article  CAS  PubMed  Google Scholar 

  108. Zeng ZH et al (2019) MicroRNA132 mediates proliferation and migration of pulmonary smooth muscle cells via targeting PTEN. Mol Med Rep 19(5):3823–3830

    CAS  PubMed  Google Scholar 

  109. Tao W et al (2019) miR-205-5p suppresses pulmonary vascular smooth muscle cell proliferation by targeting MICAL2-mediated Erk1/2 signaling. Microvasc Res 124:43–50

    Article  CAS  PubMed  Google Scholar 

  110. Xing Y et al (2015) MicroRNA-30c contributes to the development of hypoxia pulmonary hypertension by inhibiting platelet-derived growth factor receptor beta expression. Int J Biochem Cell Biol 64:155–166

    Article  CAS  PubMed  Google Scholar 

  111. Rhodes CJ et al (2013) Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 187(3):294–302

    Article  CAS  PubMed  Google Scholar 

  112. Li Y et al (2019) MicroRNA-150 relieves vascular remodeling and fibrosis in hypoxia-induced pulmonary hypertension. Biomed Pharmacother 109:1740–1749

    Article  CAS  PubMed  Google Scholar 

  113. Chen M et al (2017) MicroRNA-150 attenuates hypoxia-induced excessive proliferation and migration of pulmonary arterial smooth muscle cells through reducing HIF-1alpha expression. Biomed Pharmacother 93:861–868

    Article  CAS  PubMed  Google Scholar 

  114. Lu Z et al (2016) Upregulated miR-17 regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation and apoptosis by targeting mitofusin 2. Med Sci Monit 22:3301–3308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Liu G et al (2018) Upregulation of microRNA-17-5p contributes to hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of p21 and PTEN. Respir Res 19(1):200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pullamsetti SS et al (2012) Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med 185(4):409–419

    Article  CAS  PubMed  Google Scholar 

  117. Li H et al (2020) MicroRNA-17 as a potential diagnostic biomarker in pulmonary arterial hypertension. J Int Med Res 48(6):300060520920430

    Article  CAS  PubMed  Google Scholar 

  118. Rothman AM et al (2016) MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J Clin Invest 126(7):2495–2508

    Article  PubMed  PubMed Central  Google Scholar 

  119. Zhang Y, Xu J (2016) MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1 and promoting SOD2 expression. Biochem Biophys Res Commun 473(1):342–348

    Article  CAS  PubMed  Google Scholar 

  120. Zhu TT et al (2019) MicroRNA-140-5p targeting tumor necrosis factor-alpha prevents pulmonary arterial hypertension. J Cell Physiol 234(6):9535–9550

    Article  CAS  PubMed  Google Scholar 

  121. Yan Y et al (2020) MicroRNA-221 promotes proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) by targeting tissue inhibitor of metalloproteinases-3 (TIMP3). Cardiovasc Diagn Ther 10(4):646–657

    Article  PubMed  PubMed Central  Google Scholar 

  122. Nie X et al (2019) MicroRNA-221-3p promotes pulmonary artery smooth muscle cells proliferation by targeting AXIN2 during pulmonary arterial hypertension. Vasc Pharmacol 116:24–35

    Article  CAS  Google Scholar 

  123. Sharma S et al (2014) Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p. Circulation 130(9):776–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Xiao T et al (2017) Differential expression of microRNA in the lungs of rats with pulmonary arterial hypertension. Mol Med Rep 15(2):591–596

    Article  CAS  PubMed  Google Scholar 

  125. Zehendner CM et al (2020) Long noncoding RNA TYKRIL plays a role in pulmonary hypertension via the p53-mediated regulation of PDGFRbeta. Am J Respir Crit Care Med 202(10):1445–1457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jandl K et al (2019) Long non-coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1-AS1. J Pathol 247(3):357–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lei S et al (2020) LncRNA-SMILR modulates RhoA/ROCK signaling by targeting miR-141 to regulate vascular remodeling in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 319(2):H377–H391

    Article  CAS  PubMed  Google Scholar 

  128. Sun Z et al (2017) Long non-coding RNA MEG3 downregulation triggers human pulmonary artery smooth muscle cell proliferation and migration via the p53 signaling pathway. Cell Physiol Biochem 42(6):2569–2581

    Article  CAS  PubMed  Google Scholar 

  129. Zhu B et al (2018) Down-regulation of lncRNA MEG3 promotes hypoxia-induced human pulmonary artery smooth muscle cell proliferation and migration via repressing PTEN by sponging miR-21. Biochem Biophys Res Commun 495(3):2125–2132

    Article  CAS  PubMed  Google Scholar 

  130. Xing Y et al (2019) Long noncoding RNA-maternally expressed gene 3 contributes to hypoxic pulmonary hypertension. Mol Ther 27(12):2166–2181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gong J et al (2019) Long non-coding RNA CASC2 suppresses pulmonary artery smooth muscle cell proliferation and phenotypic switch in hypoxia-induced pulmonary hypertension. Respir Res 20(1):53

    Article  PubMed  PubMed Central  Google Scholar 

  132. Yang L et al (2019) LncRNA Tug1 involves in the pulmonary vascular remodeling in mice with hypoxic pulmonary hypertension via the microRNA-374c-mediated Foxc1. Life Sci 237:116769

    Article  CAS  PubMed  Google Scholar 

  133. Wang S et al (2019) TUG1 regulates pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension. Can J Cardiol 35(11):1534–1545

    Article  PubMed  Google Scholar 

  134. Su H et al (2018) LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT1R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension. Respir Res 19(1):254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Leisegang MS et al (2017) Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation 136(1):65–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wang S, Zhang C, Zhang X (2020) Downregulation of long noncoding RNA ANRIL promotes proliferation and migration in hypoxic human pulmonary artery smooth muscle cells. Mol Med Rep 21(2):589–596

    CAS  PubMed  Google Scholar 

  137. Zhang H et al (2019) Long noncoding RNA Hoxaas3 contributes to hypoxia-induced pulmonary artery smooth muscle cell proliferation. Cardiovasc Res 115(3):647–657

    Article  CAS  PubMed  Google Scholar 

  138. Wang D et al (2019) Long noncoding RNA MALAT1 sponges miR1243p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension. Int J Mol Med 44(3):871–884

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhu TT et al (2019) Long noncoding RNA UCA1 promotes the proliferation of hypoxic human pulmonary artery smooth muscle cells. Pflugers Arch 471(2):347–355

    Article  CAS  PubMed  Google Scholar 

  140. Liu Y et al (2018) LncRNA-TCONS_00034812 in cell proliferation and apoptosis of pulmonary artery smooth muscle cells and its mechanism. J Cell Physiol 233(6):4801–4814

    Article  CAS  PubMed  Google Scholar 

  141. Cheng G, He L, Zhang Y (2020) LincRNA-Cox2 promotes pulmonary arterial hypertension by regulating the let-7a-mediated STAT3 signaling pathway. Mol Cell Biochem

    Google Scholar 

  142. Liu Y et al (2020) Long noncoding RNA Rps4l mediates the proliferation of hypoxic pulmonary artery smooth muscle cells. Hypertension 76(4):1124–1133

    Article  CAS  PubMed  Google Scholar 

  143. Chen J et al (2018) The long noncoding RNA LnRPT is regulated by PDGF-BB and modulates the proliferation of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 58(2):181–193

    Article  CAS  PubMed  Google Scholar 

  144. Wang H, Qin R, Cheng Y (2020) LncRNA-Ang362 promotes pulmonary arterial hypertension by regulating miR-221 and miR-222. Shock 53(6):723–729

    Article  CAS  PubMed  Google Scholar 

  145. McMurtry MS et al (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95(8):830–840

    Article  CAS  PubMed  Google Scholar 

  146. Michelakis ED 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 

  147. Michelakis ED et al (2017) Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Sci Transl Med 9(413)

    Google Scholar 

  148. Khan SS et al (2015) Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study. Pulm Circ 5(3):547–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Dean A et al (2016) Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension 68(2):446–454

    Article  CAS  PubMed  Google Scholar 

  150. Liu Y et al (2019) Metformin prevents progression of experimental pulmonary hypertension via inhibition of autophagy and activation of adenosine monophosphate-activated protein kinase. J Vasc Res 56(3):117–128

    Article  CAS  PubMed  Google Scholar 

  151. Hemnes AR et al (2014) Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 189(3):325–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Pullamsetti SS et al (2014) Novel and emerging therapies for pulmonary hypertension. Am J Respir Crit Care Med 189(4):394–400

    Article  CAS  PubMed  Google Scholar 

  153. Hoeper MM et al (2013) Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 127(10):1128–1138

    Article  CAS  PubMed  Google Scholar 

  154. Montani D et al (2012) Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125(17):2128–2137

    Article  CAS  PubMed  Google Scholar 

  155. Orlikow E, Weatherald J, Hirani N (2019) Dasatinib-induced pulmonary arterial hypertension. Can J Cardiol 35(11):1604.e1–1604.e3

    Article  Google Scholar 

  156. McGee M et al (2018) Drug-associated pulmonary arterial hypertension. Clin Toxicol (Phila) 56(9):801–809

    Article  CAS  Google Scholar 

  157. Dahal BK et al (2010) Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 181(2):158–167

    Article  CAS  PubMed  Google Scholar 

  158. Izikki M et al (2009) Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 119(3):512–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Abe K et al (2004) Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 94(3):385–393

    Article  CAS  PubMed  Google Scholar 

  160. Abe K et al (2006) Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol 48(6):280–285

    Article  CAS  PubMed  Google Scholar 

  161. Mouchaers KT et al (2010) Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil. Eur Respir J 36(4):800–807

    Article  CAS  PubMed  Google Scholar 

  162. Qi L et al (2019) Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats. Bioorg Med Chem Lett 29(14):1812–1818

    Article  CAS  PubMed  Google Scholar 

  163. Ruan H et al (2019) The acute effects of 30 mg vs 60 mg of intravenous Fasudil on patients with congenital heart defects and severe pulmonary arterial hypertension. Congenit Heart Dis 14(4):645–650

    Article  PubMed  Google Scholar 

  164. Ruan HY, Zhang YG, Liu R (2018) [Acute effects of intravenous fasudil with different dosage on patients with congenital heart defects and severe pulmonary arterial hypertension]. Zhonghua Yi Xue Za Zhi 98(9):678–681

    Google Scholar 

  165. Xiao JW et al (2015) Acute effects of Rho-kinase inhibitor fasudil on pulmonary arterial hypertension in patients with congenital heart defects. Circ J 79(6):1342–1348

    Article  CAS  PubMed  Google Scholar 

  166. Houssaini A, Adnot S (2017) mTOR: a key to both pulmonary vessel remodeling and right ventricular function in pulmonary arterial hypertension? Am J Respir Cell Mol Biol 57(5):509–511

    Article  CAS  PubMed  Google Scholar 

  167. Seyfarth HJ et al (2013) Everolimus in patients with severe pulmonary hypertension: a safety and efficacy pilot trial. Pulm Circ 3(3):632–638

    Article  PubMed  PubMed Central  Google Scholar 

  168. Segura-Ibarra V et al (2017) Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension. Int J Pharm 524(1–2):257–267

    Article  CAS  PubMed  Google Scholar 

  169. Tang H et al (2018) Pathogenic role of mTORC1 and mTORC2 in pulmonary hypertension. JACC Basic Transl Sci 3(6):744–762

    Article  PubMed  PubMed Central  Google Scholar 

  170. Ranchoux B et al (2015) Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131(11):1006–1018

    Article  CAS  PubMed  Google Scholar 

  171. Tsutsumi T et al (2019) Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation. PLoS One 14(7):e0214697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Rabinovitch M et al (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115(1):165–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Trankle CR et al (2019) IL-1 blockade reduces inflammation in pulmonary arterial hypertension and right ventricular failure: a single-arm, open-label, phase IB/II pilot study. Am J Respir Crit Care Med 199(3):381–384

    Article  PubMed  PubMed Central  Google Scholar 

  174. Cheng Y et al (2018) Identification of a novel hybridization from isosorbide 5-mononitrate and bardoxolone methyl with dual activities of pulmonary vasodilation and vascular remodeling inhibition on pulmonary arterial hypertension rats. J Med Chem 61(4):1474–1482

    Article  CAS  PubMed  Google Scholar 

  175. Nickel NP et al (2015) Elafin reverses pulmonary hypertension via caveolin-1-dependent bone morphogenetic protein signaling. Am J Respir Crit Care Med 191(11):1273–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Good RB et al (2015) Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol 185(7):1850–1858

    Article  CAS  PubMed  Google Scholar 

  177. Ranchoux B et al (2018) Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series). Pulm Circ 8(1):2045893217752912

    Article  PubMed  CAS  Google Scholar 

  178. Qiao L et al (2014) Endothelial fate mapping in mice with pulmonary hypertension. Circulation 129(6):692–703

    Article  CAS  PubMed  Google Scholar 

  179. Hopper RK et al (2016) In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug. Circulation 133(18):1783–1794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Huang J et al (2020) Transplantation of mesenchymal stem cells attenuates pulmonary hypertension by normalizing the endothelial-to-mesenchymal transition. Am J Respir Cell Mol Biol 62(1):49–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Xu J et al (2018) Dipeptidyl peptidase IV (DPP-4) inhibition alleviates pulmonary arterial remodeling in experimental pulmonary hypertension. Lab Investig 98(10):1333–1346

    Article  CAS  PubMed  Google Scholar 

  182. Zhang H et al (2019) Protective effect of hydrogen sulfide on monocrotaline-induced pulmonary arterial hypertension via inhibition of the endothelial mesenchymal transition. Int J Mol Med 44(6):2091–2102

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Yu M et al (2020) Paeoniflorin ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition. Drug Des Devel Ther 14:1191–1202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Isobe S et al (2019) Endothelial-mesenchymal transition drives expression of CD44 variant and xCT in pulmonary hypertension. Am J Respir Cell Mol Biol 61(3):367–379

    Article  CAS  PubMed  Google Scholar 

  185. Li L et al (2017) NF-kappaB mediated miR-130a modulation in lung microvascular cell remodeling: implication in pulmonary hypertension. Exp Cell Res 359(1):235–242

    Article  CAS  PubMed  Google Scholar 

  186. Xu YP et al (2017) MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension. Hypertens Res 40(6):552–561

    Article  CAS  PubMed  Google Scholar 

  187. Zhang H et al (2018) Bone morphogenetic protein-7 inhibits endothelial-mesenchymal transition in pulmonary artery endothelial cell under hypoxia. J Cell Physiol 233(5):4077–4090

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are thankful to Dr. Adam Andruska, Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, USA, for providing guidance, for editing the chapter, and also for providing the lung section images of PAH patients and healthy controls.

Author information

Authors and Affiliations

  1. Division of Pulmonary, Allergy and Critical Care Medicine, Stanford Medical School, Stanford, CA, USA

    Md Khadem Ali & Edda F. Spiekerkoetter

  2. Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, USA

    Md Khadem Ali & Edda F. Spiekerkoetter

  3. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia

    Jay C. Horvat

Authors
  1. Md Khadem Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jay C. Horvat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edda F. Spiekerkoetter
    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

Ali, M.K., Horvat, J.C., Spiekerkoetter, E.F. (2021). Targeting Molecular and Cellular Mechanisms of Pulmonary Arterial 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_18

Download citation

Publish with us

Policies and ethics

Search

Navigation