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The role of endothelin in the pathobiology of pulmonary arterial hypertension

The role of endothelin in the pathobiology of pulmonary arterial hypertension. Robert Naeije Erasme Hospital, Faculty of Medicine, Free University of Brussels. Pulmonary arterial hypertension: a disease of the small resistive arterioles.

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The role of endothelin in the pathobiology of pulmonary arterial hypertension

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  1. The role of endothelin in the pathobiology of pulmonaryarterial hypertension Robert Naeije Erasme Hospital, Faculty of Medicine, Free University of Brussels

  2. Pulmonary arterial hypertension: a disease of the small resistive arterioles After Heath & Edwards, Circulation 1958;18:533-47 Wagenvoort & Wagenvoort, Circulation 1970; 42: 1163-84

  3. The historical notion of a vasoconstrictive factor in PAH • Demonstration of a reversible component of PVR with acetylcholine and tolazaline as soon as with initial recognition of PAH as a clinical entity Dresdale et al, Am J Med 1951; 11: 686-705 Wood et al, Br Heart J 1957; 19: 279-292 • Morphology suggestive of early reversibility in earlier stages of disease Heath & Edwards, Circulation 1958;18:533-47 Wagenvoort & Wagenvoort, Circulation 1970;42:1163-84 Palevsky et al Circulation 1989; 80: 1207-1221

  4. The pathogenesis of PAH: from vasospasms to remodelling PVR Late Vasoconstrictor factors Cells Detection limit Vasospasms Remodelling Matrix and fibrin Early P Wood Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958; 21: 557-70.

  5. Ser Ser Leu Cys Cys Ser N Met ET-1 Endothelin Asp Lys Glu Leu Val Tyr Cys Cys Phe His Asp Ile C Ile Trp • 21-amino-acid peptide isolated from cultured porcine aortic endothelial cells1, first reported in 1988 • Regulates pulmonary vascular tone, sodium balance, neural crest cell development and neurotransmission • Key mediator in pulmonary hypertension Yanagisawa M, et al. Nature 1988;3 32:411-15.

  6. Endothelin plasma levels are increased in PAH Congenitalheart disease3 Idiopathic PAH1 Scleroderma2 5 10 10 8 4 8  ET-LI (PV-RV)(pg/ml) 6 3 ET-1 (pg/ml) ET-1(pg/ml) 4 2 6 2 1 0 4 0 Non-PAH PAH Non-PPH PPH Non-PH PH 1Stewart DJ, et al. Ann Intern Med 1991;114:464-9. 2Vancheeswaran R, et al. J Rheum 1994;21:1838-44. 3Yoshibayashi M, et al. Circulation 1991;84:2280-5.

  7. Expression of endothelin-1 is increased in the lungs of patients with pulmonary hypertension Small size pulmonary artery and plexiform lesion in PAH Normal Increased immunostaining for ET-1 in small size pulmonary arteries of PAH patients, in proportion to increased PVR Giaid et al. N Engl J Med 1993;328:1732-9.

  8. Endothelin drives disease progression and determines patients‘ long-term outcome n=24 IPAH patients 1.0 ET-1  4.3 pg/ml ET-1 < 4.3 pg/ml 0.5 Survival p = 0.04 (log rank) 0.0 0 12 24 36 48 Time (months) Galiè N, et al. Eur J Clin Invest 1996;26 (Suppl 1):A48.

  9. Systemic-to-pulmonary shunting during 3 months in piglets induces pulmonary hypertension with medial hypertrophy, which is partially prevented dual ETA/ETB blockade with bosentan Rondelet B et al. Circulation 2003; 107:1329-35.

  10. Bosentan prevents overcirculation-induced PAH in piglets 60 30 Sham Sham *†‡ Placebo Placebo *†‡ Treatment Treatment *†‡ 20 40 *†‡ *† Medial thickness (%) Ppam (mmHg) *† 10 20 0 0 0 150 300 450 2 5 m External diameter ( m) -1 -2 Q ( L . min . m ) r = 0.6104 r = 0.4521 40 40 p < 0.01 p < 0.05 < 75m pulmonary arterymedial thickness (%) < 300m pulmonary arterymedial thickness (%) 20 20 0 0 10 20 30 40 10 20 30 40 Ppa (mmHg) Ppa (mmHg) m m Rondelet B et al. Circulation 2003; 107:1329-35, Circulation 2004,110:2220-5

  11. 80 60 40 20 0 -20 -40 Dual endothelin A and B receptor blockade by bosentan improves PAH patients Bosentan (n = 144) Placebo (n = 69)  Walk Distance(meters) p = 0.0002 Mean ± SEM Baseline Week 4 Week 8 Week 16 125 or 250 mg/bid 62.5 mg/bid Rubin LJ et al. N Engl J Med 2002; 346: 896-903.

  12. - - - + Pulmonary circulation: ET-1 as a key mediator in endothelial maintainance of tone and structure Endothelin pathway NO pathway Prostacyclin pathway Arachidonic acid  PgI2 Pre-pro-ET pro-ET L-arginine L-citrulline Endothelin receptor antagonists Prostacyclin (PgI2 ) Endothlin-1 Prostacyclin derivatives Nitric oxide ETA ETB AMPc vasodilatation anti-proliferation cGMP vasoconstriction proliferation vasodilatation anti-proliferation PDE5 PDE5 inhibitors

  13. Biological theories of PAH Endothelium-derived vasoconstrictor/dilator imbalance (ET-1/PGI2-NO): increased expression of ET-1, decreased expressions of PGI2 and NO synthases, efficacy of targeted therapies Gaine SP, Rubin LJ. Lancet 1998; 352: 719-725 Serotonin receptors (5HT 1B, 2B and 2A) and transporter (anorexigens) Eddahibi et al, J Clin Invest 2001; 108: 1141-50 Other: Decreased PASM potassium channels, increased PDE5, inflammation, misguided angiogenesis Humbert et al, JACC 2004; 43suppl: 13S-24S

  14. Genetics IPAH: > 6 % familial, autosomal dominant pattern of inheritance with reduced penetrance Mutation in gene encoding for bone morphogenetic protein receptor 2 (BMPR2) in 16 of 27 IPAH families Deng et al, Am J Human Genet 2000;67:737-44, and Internat PPH Consortium Nat Genet 2000;26:81-4 BMP’s are members of the TGF superfamily BMPR2-smad signalling inhibits proliferation

  15. BMPR2 mutations as a cause of PAH • Estimated < 10 – 20 % incidence of PAH in carriers of BMPR2 mutations • Not all familial PAH have detectable BMPR2 mutations • Incidence of BMPR2 mutations 5 % in sporadic IPAH • BMPR2 mutations uncommon in other PAH categories (anorexigens, CHD) BMPR2 mutations neither necessary nor sufficient

  16. Decreased BMPR2 protein in IPAH with BMPR2 mutations > IPAH > CHD or CTD - PAH Atkinson et al, Circulation 2002;105: 1672-78

  17. Signaling molecules in nonfamilial pulmonary hypertension Lingling Du et al, N Engl J Med 2003; 348: 500-509 Increased expression of angiopoietin-1 in the lungs of patients with various forms of severe pulmonary hypertension: 22 CTEPH, 5 IPAH, 3 CTD-associated PAH, 3 Eisenmenger, 9 mitral valve disease-associated PH Angiopoietin-1 shuts of the expression of BMPR1A, a transmembrane protein required for BMPR2 signalling

  18. Ang-1–Band Density r = 0.97 p≤ 0.001 1.0 0.8 0.6 0.4 0.2 0.0 0 500 1000 1500 2000 Pulmonary Vascular Resistance (dyn•sec•cm-5) Lingling Du et al, N Engl J Med 2003; 348: 500-9.

  19. Central role for the angiopoietin-1 / BMPR2 pathway in the pathogenesis of PAH BMPR2 mutation Angiopoietin-1 - - - Other factors Cytokines? BMPR2 receptor - Smad signalling Unrestricted PVSMC proliferation Pulmonary arterial hyprtension

  20. Expression of ET-1, ETB, angiopoietin-1 and BMPR2 in a piglet model of CHD-PAH R = 0.7074 20.103 R = 0.5675 10 p < 0.001 p < 0.01 ET-1 mRNA lung content (2-DCt) Ang-1 mRNA lungcontent (2-DCt) Ppam(mmHg) 0 0 0 10 20 30 40 50 0 10 20 30 40 50 20 R = 0.3792 R = 0.5357 70 p = NS p < 0.01 ET-B mRNA lung content (2-DCt) BMPR2 mRNA lungcontent (2-DCt) Ppam(mmHg) 0 0 0 10 20 30 40 50 0 10 20 30 40 50 Rondelet B et al. Circulation 2003; 107:1329-35, Circulation 2004; 110:2220-5.

  21. Signalling molecules in experimental overcirculation-induced PAH • Endothelial imbalance: Increased expressions of ET-1 / ETB receptor, and PDE5 • Angiogenesis/inflammation: Increased expressions of angiopoietin-1, VEGF, angiotensin-II, MCP-1 and ICAM • Serotonin: increased expression of 5HT1B • Decreased expressions of BMPR2 and BMPR1A Rondelet B et al. Circulation 2003; 107:1329-35, 2004; 110:2220-5.

  22. Induction of pulmonary hypertension by an angiopoietin-1/TIE2/serotonin pathwaySullivan CC et al, PNAS; 2004; 100: 12331-6 Rodents engineerd to express angiopoietin-1 in the lung develop severe pulmonary hypertension (medial thickening) Angiopoietin-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 receptor pathway to produce serotonin High levels of serotonin found in human and rodent pulmonary hypertensive lung tissue

  23. Sullivan CC, et al. PNAS 2003;100: 12331-6.

  24. Contribution of the angiopoietin-1/Tie2 pathway to pulmonary artery smooth muscle hyperplasia in IPAH Dewachter L et al, PATS 2005; 2: A710 • Lung tissue from 14 patients with IPAH, 9 patients with SPH, and 15 controls • RT-PCR, immunohistology, Western blotting • Cultured pulmonary artery endothelial and smooth muscle cells • Treatment of the endothelial cells with human recombinant angiopoietin-1, and mesurement of supernatant ET-1, 5HT, EGF and PDGF

  25. SPH IPH IPH SPH CT CT Tie2 b - Actin 42 kD * 140 kD ** B A Overexpression of Tie2 in IPAH

  26. * * A B * * Tie2 receptor in cultured pulmonary endothelial from IPAH and SPH patients

  27. B A D C Pulmonary artery endothelial cells treated with angiopoietin-1

  28. BMPR2 / TIE2 : loss of endothelial control of inflammation-angiogenesis - related remodelling ET-1, MCP1, ICAM, VEGF angiopoietin-1, angiotensin II decreased PGI2 and NO BMPR2 mutation - - + BMPR2 receptor Tie2 receptor - Smad signalling Unrestricted PVSMC proliferation Pulmonary arterial hypertension 5HT, ET-1

  29. Conclusions The pathobiology of PAH remains mysterious Central: abnormal BMPR2 and Tie2 signaling, with excess endothelial-derived ET-1 + 5HT and insufficient endothelium-derived PGI2 + NO possibly triggered by injury-repair reaction (inflammation-angiogenesis) Restoration of endothelial equilibrium by the dual ET-1 receptor blocker bosentan partially prevents experimental PAH, and is effective palliative therapy in PAH patients

  30. Acknowledgments ULBINSERM U651, Créteil Benoît Rondelet Laurence Dewachter Serge Brimioulle Saadia Eddahibi Ronald Van Beneden Serge Adnot Sophie Motte Marc Humbert Isabelle Salmon Myriam Remmelink VUB Ives Hubloue Marseille François Kerbaul

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