Skip to main content
SpringerLink
Log in
Book cover

Membrane Receptors, Channels and Transporters in Pulmonary Circulation pp 447–458Cite as

PPARγ and the Pathobiology of Pulmonary Arterial Hypertension

  • Conference paper
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((volume 661))

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that functions as a transcription factor to regulate adipogenesis and metabolism by binding to PPAR response elements (PPAREs) in the promoter region of various target genes. Activation of PPARγ suppresses smooth muscle cell proliferation and migration. This chapter discusses the potential protective role of PPARγ and its downstream signaling cascades in the development of pulmonary arterial hypertension. Furthermore, the chapter also provides an overview on the cellular and molecular mechanisms involved in PPARγ-mediated inhibitory effect on pulmonary vascular remodeling, a major contributor to the elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension.

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   189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
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. He W, Barak Y, Hevener A et al (2003) Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A 100:15712-15717

    Article  PubMed  CAS  Google Scholar 

  2. Hevener AL, He W, Barak Y et al (2003) Muscle-specific PPARγ deletion causes insulin resistance. Nat Med 9:1491-1497

    Article  PubMed  CAS  Google Scholar 

  3. Lehrke M, Lazar MA (2005) The many faces of PPARγ. Cell 123:993-999

    Article  PubMed  CAS  Google Scholar 

  4. Marx N, Duez H, Fruchart JC, Staels B (2004) Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res 94:1168-1178

    Article  PubMed  CAS  Google Scholar 

  5. Zhang J, Fu M, Zhao L, Chen YE 2002) 15-Deoxy-prostaglandin J2 inhibits PDGF-A and -B chain expression in human vascular endothelial cells independent of PPARγ. Biochem Biophys Res Commun 298:128-132

    Article  PubMed  CAS  Google Scholar 

  6. Gauthier A, Vassiliou G, Benoist F, McPherson R (2003) Adipocyte low density lipoprotein receptor-related protein gene expression and function is regulated by peroxisome proliferator-activated receptor γ. J Biol Chem 278:11945-11953

    Article  PubMed  CAS  Google Scholar 

  7. Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J (2003) LRP: role in vascular wall integrity and protection from atherosclerosis. Science 300:329-332

    Article  PubMed  CAS  Google Scholar 

  8. Newton CS, Loukinova E, Mikhailenko I et al (2005) Platelet-derived growth factor receptor-β (PDGFR-β) activation promotes its association with the low density lipoprotein receptor-related protein (LRP). Evidence for co-receptor function. J Biol Chem 280:27872-27878

    Article  PubMed  CAS  Google Scholar 

  9. Wakino S, Kintscher U, Kim S, Yin F, Hsueh WA, Law RE (2000) Peroxisome proliferator-activated receptor γ ligands inhibit retinoblastoma phosphorylation and G1 → S transition in vascular smooth muscle cells. J Biol Chem 275:22435-22441

    Article  PubMed  CAS  Google Scholar 

  10. Bruemmer D, Blaschke F, Law RE (2005) New targets for PPARγ in the vessel wall: implications for restenosis. Int J Obes Relat Metab Disord 29:S26-S30

    Article  CAS  Google Scholar 

  11. Benkirane K, Amiri F, Diep QN, El Mabrouk M, Schiffrin EL (2006) PPAR-γ inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1. Am J Physiol Heart Circ Physiol 290:H390-H397

    Article  PubMed  CAS  Google Scholar 

  12. Wakino S, Kintscher U, Liu Z et al (2001) Peroxisome proliferator-activated receptor γ ligands inhibit mitogenic induction of p21Cip1 by modulating the protein kinase Cδ pathway in vascular smooth muscle cells. J Biol Chem 276:47650-47657

    Article  PubMed  CAS  Google Scholar 

  13. Ogawa D, Nomiyama T, Nakamachi T et al (2006) Activation of peroxisome proliferator-activated receptor γ suppresses telomerase activity in vascular smooth muscle cells. Circ Res 98:e50-e9

    Article  PubMed  CAS  Google Scholar 

  14. Vantler M, Caglayan E, Zimmermann WH, Baumer AT, Rosenkranz S (2005) Systematic evaluation of anti-apoptotic growth factor signaling in vascular smooth muscle cells. Only phosphatidylinositol 3′-kinase is important. J Biol Chem 280:14168-14176

    Article  PubMed  CAS  Google Scholar 

  15. Bruemmer D, Yin F, Liu J et al (2003) Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res 93:e38-e47

    Article  PubMed  CAS  Google Scholar 

  16. Worley JR, Baugh MD, Hughes DA et al (2003) Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonists and 9-cis-retinoic acid. J Biol Chem 278:51340-51346

    Article  PubMed  CAS  Google Scholar 

  17. Nagase H, Enghild J, Suzuki K, Salvesen G (1990) Stepwise activation mechanisms of the precursor of matrix metalloproteinase 3 (stromelysin) by proteinases and (4-aminophenyl) mercuric acetate. Biochemistry 29:5783-5789

    Article  PubMed  CAS  Google Scholar 

  18. 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 6:698-702

    Article  PubMed  CAS  Google Scholar 

  19. Martin-Nizard F, Furman C, Delerive P et al (2002) Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. J Cardiovasc Pharmacol 40:822-831

    Article  PubMed  CAS  Google Scholar 

  20. Wakino S, Hayashi K, Tatematsu S et al (2005) Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens Res 28:255-262

    Article  PubMed  CAS  Google Scholar 

  21. Kielstein JT, Bode-Boger SM, Hesse G et al (2005) Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 25:1414-1418

    Article  PubMed  CAS  Google Scholar 

  22. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mechanisms in Alzheimer’s disease: inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J Neurosci 20:558-567

    PubMed  CAS  Google Scholar 

  23. Humbert M, Monti G, Brenot F et al (1995) Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151:1628-1631

    PubMed  CAS  Google Scholar 

  24. Imaizumi T, Matsumiya T, Tamo W et al ( 2002) 15-Deoxy-D12,14-prostaglandin J2 inhibits CX3CL1/fractalkine expression in human endothelial cells. Immunol Cell Biol 80:531-536

    Article  PubMed  CAS  Google Scholar 

  25. Balabanian K, Foussat A, Dorfmüller P et al (2002) CX3C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 165:1419-1425

    Article  PubMed  Google Scholar 

  26. Ikeda Y, Yonemitsu Y, Kataoka C et al (2002) Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 283:H2021-H2028

    PubMed  CAS  Google Scholar 

  27. Gensch C, Clever YP, Werner C, Hanhoun M, Böhm M, Laufs U (2007) The PPAR-γ agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis 192:67-74

    Article  PubMed  CAS  Google Scholar 

  28. Levonen AL, Dickinson DA, Moellering DR, Mulcahy RT, Forman HJ, Darley-Usmar VM (2001) Biphasic effects of 15-deoxy-δ12,14-prostaglandin J2 on glutathione induction and apoptosis in human endothelial cells. Arterioscler Thromb Vasc Biol 21:1846-1851

    Article  PubMed  CAS  Google Scholar 

  29. Cho DH, Choi YJ, Jo SA, Jo I (2004) Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) γ-dependent and PPAR γ-independent signaling pathways. J Biol Chem 279:2499-2506

    Article  PubMed  CAS  Google Scholar 

  30. Kronke G, Kadl A, Ikonomu E et al (2007) Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol 27:1276-1282

    Article  PubMed  Google Scholar 

  31. Goetze S, Xi XP, Kawano H et al (1999) PPARγ-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. J Cardiovasc Pharmacol 33:798-806

    Article  PubMed  CAS  Google Scholar 

  32. Benson S, Wu J, Padmanabhan S, Kurtz TW, Pershadsingh HA (2000) Peroxisome proliferator-activated receptor (PPAR)-γ expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-γ activator troglitazone. Am J Hypertens 13:74-82

    Article  PubMed  CAS  Google Scholar 

  33. Law RE, Goetze S, Xi XP et al (2000) Expression and function of PPARγ in rat and human vascular smooth muscle cells. Circulation 101:1311-1318

    Article  PubMed  CAS  Google Scholar 

  34. Ameshima S, Golpon H, Cool CD et al (2003) Peroxisome proliferator-activated receptor γ (PPARγ) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 92:1162-1169

    Article  PubMed  CAS  Google Scholar 

  35. Geraci MW, Moore M, Gesell T et al (2001) Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res 88:555-562

    Article  PubMed  CAS  Google Scholar 

  36. Galetto R, Albajar M, Polanco JI, Zakin MM, Rodriguez-Rey JC (2001) Identification of a peroxisome-proliferator-activated-receptor response element in the apolipoprotein E gene control region. Biochem J 357:521-527

    Article  PubMed  CAS  Google Scholar 

  37. Akiyama TE, Sakai S, Lambert G et al (2002) Conditional disruption of the peroxisome proliferator-activated receptor γ gene in mice results in lowered expression of ABCA1, ABCG1, and ApoE in macrophages and reduced cholesterol efflux. Mol Cell Biol 22:2607-2619

    Article  PubMed  CAS  Google Scholar 

  38. Yue L, Rasouli N, Ranganathan G, Kern PA, Mazzone T (2004) Divergent effects of peroxisome proliferator-activated receptor γ agonists and tumor necrosis factor α on adipocyte ApoE expression. J Biol Chem 279:47626-47632

    Article  PubMed  CAS  Google Scholar 

  39. Hansmann G, Wagner RA, Schellong S et al (2007) Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-γ activation. Circulation 115:1275-1284

    PubMed  CAS  Google Scholar 

  40. Xu A, Chan KW, Hoo RL et al (2005) Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 280:18073-18080

    Article  PubMed  CAS  Google Scholar 

  41. Wang Y, Lam KS, Xu JY et al (2005) Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J Biol Chem 280:18341-18347

    Article  PubMed  CAS  Google Scholar 

  42. Swertfeger DK, Bu G, Hui DY (2002) Low density lipoprotein receptor-related protein mediates apolipoprotein E inhibition of smooth muscle cell migration. J Biol Chem 277:4141-4146

    Article  PubMed  CAS  Google Scholar 

  43. Boucher P, Gotthardt M (2004) LRP and PDGF signaling: a pathway to atherosclerosis. Trends Cardiovasc Med 14:55-60

    Article  PubMed  CAS  Google Scholar 

  44. Boucher P, Liu P, Gotthardt M, Hiesberger T, Anderson RG, Herz J (2002) Platelet-derived growth factor mediates tyrosine phosphorylation of the cytoplasmic domain of the low density lipoprotein receptor-related protein in caveolae. J Biol Chem 277:15507-15513

    Article  PubMed  CAS  Google Scholar 

  45. Wilkinson-Berka JL, Babic S, De Gooyer T et al (2004) Inhibition of platelet-derived growth factor promotes pericyte loss and angiogenesis in ischemic retinopathy. Am J Pathol 164:1263-1273

    Article  PubMed  CAS  Google Scholar 

  46. Zamanian RT, Hansmann G, Snook S et al (2009) Insulin resistance in pulmonary arterial hypertension. Eur Respir J 33:318-324

    Article  PubMed  CAS  Google Scholar 

  47. Lane KB, Machado RD, Pauciulo MW et al (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81-84

    Article  PubMed  CAS  Google Scholar 

  48. Deng Z, Morse JH, Slager SL et al (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737-744

    Article  PubMed  CAS  Google Scholar 

  49. Machado RD, Aldred MA, James V et al (2006) Mutations of the TGF-β type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121-132

    Article  PubMed  CAS  Google Scholar 

  50. Atkinson C, Stewart S, Upton PD et al (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105:1672-1678

    Article  PubMed  CAS  Google Scholar 

  51. Hansmann G, de Jesus Perez VA, Alastalo TP et al (2008) An antiproliferative BMP-2/PPARγ/ApoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 118:1846-1857

    Article  PubMed  CAS  Google Scholar 

  52. Crossno JT Jr, Garat CV, Reusch JE et al (2007) Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol Lung Cell Mol Physiol 292:L885-L897

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, CA, USA

    Marlene Rabinovitch

Authors
  1. Marlene Rabinovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marlene Rabinovitch .

Editor information

Editors and Affiliations

  1. Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, 60612, USA

    Jason X. -J. Yuan

  2. Guy’s Hospital Campus, Dept. Physiology, King’s College London, London, SE1 1UL, United Kingdom

    Jeremy P. T. Ward

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this paper

Cite this paper

Rabinovitch, M. (2010). PPARγ and the Pathobiology of Pulmonary Arterial Hypertension. In: Yuan, JJ., Ward, J. (eds) Membrane Receptors, Channels and Transporters in Pulmonary Circulation. Advances in Experimental Medicine and Biology, vol 661. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-500-2_29

Download citation

Publish with us

Policies and ethics

Search

Navigation