New therapies for pulmonary arterial hypertension: An update on current bench to bedside translation

Expert Opinion on Investigational Drugs

Volumn 19, Issue 4, 2010, Pages 469-488

  Dewachter, Laurence ^a   Dewachter, Céline ^a   Naeije, Robert ^a  

^a FREE UNIVERSITY OF BRUSSELS   (Belgium)

Author keywords

Anti inflammatory; Anti remodeling; Emerging drugs; New targets; Pulmonary hypertension; Treatment

Indexed keywords

1 BENZYL 3 (5 HYDROXYMETHYL 2 FURYL)INDAZOLE; 4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; 4 [[4 CARBOXYBUTYL[2 [(4 PHENETHYLBENZYL)OXY]PHENETHYL]AMINO]METHYL]BENZOIC ACID; ADRENOMEDULLIN; ATORVASTATIN; BAY 420 2272; BAY 63 2521; CYCLOSPORIN A; DICHLOROACETIC ACID; ELASTASE INHIBITOR; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENDOTHELIN RECEPTOR ANTAGONIST; ESCITALOPRAM; FASUDIL; FLUOXETINE; GUANYLATE CYCLASE ACTIVATOR; IMATINIB; PAROXETINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PHOSPHODIESTERASE V INHIBITOR; PROSTACYCLIN; PROTEIN INHIBITOR; PROTEIN TYROSINE KINASE INHIBITOR; RIOCIGUAT; ROSIGLITAZONE; ROSUVASTATIN; SIMVASTATIN; SORAFENIB; SURVIVIN ANTAGONIST; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASOACTIVE INTESTINAL POLYPEPTIDE; ANTIHYPERTENSIVE AGENT;

APOPTOSIS; BLOOD VESSEL TONE; BREAST CANCER; CELL PROLIFERATION; CLINICAL TRIAL; DISEASE SEVERITY; DOWN REGULATION; DRUG ACTIVITY; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ENZYME DEGRADATION; GLUCOSE OXIDATION; HEART RIGHT VENTRICLE FUNCTION; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; LACTIC ACIDOSIS; LIFE EXPECTANCY; LUNG ARTERY PRESSURE; LUNG NON SMALL CELL CANCER; MORTALITY; NONHUMAN; OXIDATIVE STRESS; PULMONARY HYPERTENSION; QUALITY OF LIFE; REVIEW; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; SURVIVAL RATE; VASCULAR RESISTANCE; ANIMAL; CLINICAL TRIAL (TOPIC); DRUG EFFECTS; HOSPITAL INFORMATION SYSTEM; HYPERTENSION, PULMONARY; PATHOLOGY; PATHOPHYSIOLOGY; PULMONARY ARTERY; TRENDS;

ANIMALS; ANTIHYPERTENSIVE AGENTS; CLINICAL TRIALS AS TOPIC; HUMANS; HYPERTENSION, PULMONARY; POINT-OF-CARE SYSTEMS; PULMONARY ARTERY;

EID: 77952492039     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543781003727099     Document Type: Review

References (179)

1. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55-66
2. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54
3. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S78-84
4. Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008;51:1527-1538
5. van Wolferen SA, Marcus JT, Boonstra A, et al. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 2007;28:1250-1257
6. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009;54:S10-19
7. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S20-31
8. Machado RD, Eickelberg O, Elliott CG, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S32-42
9. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105-3111
10. Ghofrani HA, Barst RJ, Benza RL, et al. Future perspectives for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S108-117
11. Michelakis ED, Wilkins MR, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation 2008;118:1486-1495
12. Michelakis ED, McMurtry MS, Wu XC, et al. 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 2002;105:244-250
13. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:1400-1406 (Pubitemid 28462800)
14. McMurtry MS, Bonnet S, Wu X, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004;95:830-840
15. Piao L, Fang YH, Cadete VJ, et al. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 2010;88:47-60
16. Zhang TT, Cui B, Dai DZ. Downregulation of Kv4.2 and Kv4.3 channel gene expression in right ventricular hypertrophy induced by monocrotaline in rat. Acta Pharmacol Sin 2004;25:226-230
17. Bonnet S, Michelakis ED, Porter CJ, et al. 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 2006;113:2630-2641
18. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007;11:37-51
19. Moudgil R, Michelakis ED, Archer SL. 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 2006;13:615-632
20. Guignabert C, Tu L, Izikki M, et al. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J 2009;23:4135-4147
21. Nagendran J, Gurtu V, Fu DZ, et al. A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. J Thorac Cardiovasc Surg 2008;136:168-178
22. de Frutos S, Spangler R, Alo D, et al. NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation. J Biol Chem 2007;282:15081-15089
23. Bonnet S, Rochefort G, Sutendra G, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 2007;104:11418-11423
24. Pu WT, Ma Q, Izumo S. NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circ Res 2003;92:725-731
25. Rossow CF, Minami E, Chase EG, et al. NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction. Circ Res 2004;94:1340-1350
26. Wang C, Li JF, Zhao L, et al. Inhibition of SOC/Ca2+/NFAT pathway is involved in the anti-proliferative effect of sildenafil on pulmonary artery smooth muscle cells. Respir Res 2009;10:123
27. McMurtry MS, Archer SL, Altieri DC, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005;115:1479-1491
28. Blanc-Brude OP, Yu J, Simosa H, et al. Inhibitor of apoptosis protein survivin regulates vascular injury. Nat Med 2002;8:987-994
29. Wang GJ, Sui XX, Simosa HF, et al. Regulation of vein graft hyperplasia by survivin, an inhibitor of apoptosis protein. Arterioscler Thromb Vasc Biol 2005;25:2081-2087
30. Plescia J, Salz W, Xia F, et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 2005;7:457-468
31. Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 2007;115:1275-1284
32. Guignabert C, Alvira CM, Alastalo TP, et al. Tie2-mediated loss of peroxisome proliferator-activated receptor-{gamma} in mice causes PDGF-receptor {beta}-dependant pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 2009;23:4135-4147
33. Crossno JT Jr, Garat CV, Reusch JE, et al. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol Lung Cell Mol Physiol 2007;292:L885-897
34. Matsuda Y, Hoshikawa Y, Ameshima S, et al. Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats. Nihon Kokyuki Gakkai Zasshi 2005;43:283-288
35. Law RE, Goetze S, Xi XP, et al. Expression and function of PPAR-gamma in rat and human vascular smooth muscle cells. Circulation 2000;101:1311-1318
36. Falcetti E, Flavell DM, Staels B, et al. IP receptor-dependent activation of PPARgamma by stable prostacyclin analogues. Biochem Biophys Res Commun 2007;360:821-827
37. Juurlink DN, Gomes T, Lipscombe LL, et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population-based cohort study. BMJ 2009;339:b2942
38. Schermuly RT, Stasch JP, Pullamsetti SS, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008;32:881-891
39. de Frutos S, Nitta CH, Caldwell E, et al. Regulation of soluble guanylyl cyclase-alpha1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR. Am J Physiol Lung Cell Mol Physiol 2009;297:L475-486
40. Li D, Zhou N, Johns RA. Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia. Am J Physiol 1999;277:L841-847
41. Vermeersch P, Buys E, Pokreisz P, et al. Soluble guanylate cyclase-alpha1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia. Circulation 2007;116:936-943
42. Dumitrascu R, Weissmann N, Ghofrani HA, et al. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 2006;113:286-295
43. Evgenov OV, Pacher P, Schmidt PM, et al. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006;5:755-768
44. Deruelle P, Grover TR, Abman SH. Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep. Am J Physiol Lung Cell Mol Physiol 2005;289:L798-806
45. Frey R, Muck W, Unger S, et al. Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. J Clin Pharmacol 2008;48:1400-1410
46. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33:785-792
47. Yu Y, Sweeney M, Zhang S, et al. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 2003;284:C316-330
48. Perros F, Montani D, Dorfmuller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;178:81-88
49. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821
50. Smyth MJ. Imatinib mesylate\uncovering a fast track to adaptive immunity. N Engl J Med 2006;354:2282-2284
51. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412-1413 (Pubitemid 41362714)
52. Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med 2006;145:152-153
53. Souza R, Sitbon O, Parent F, et al. Long term imatinib treatment in pulmonary arterial hypertension. Thorax 2006;61:736
54. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in patients with severe pulmonary artery hypertension (PAH) refractory to standard therapy [abstract]. Am J Respir Crit Care Med 2009;179:A1044
55. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908-916
56. Klein M, Schermuly RT, Ellinghaus P, et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 2008;118:2081-2090
57. Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 2008;33:278-291
58. Gomberg-Maitland M. Tyrosine kinase inhibitors and antiangiogenesis agents in PAH: sorafenib as a therapy for PAH: results of a phase I drug dosing safety trial [abstract 388]. American Thoracic Society, Toronto; May 2008
59. Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res 2010;106:21-34
60. Fagan KA, Oka M, Bauer NR, et al. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 2004;287:L656-664
61. Nagaoka T, Fagan KA, Gebb SA, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171:494-499
62. Wang Z, Jin N, Ganguli S, et al. Rho-kinase activation is involved in hypoxia-induced pulmonary vasoconstriction. Am J Respir Cell Mol Biol 2001;25:628-635
63. Guilluy C, Eddahibi S, Agard C, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 2009;179:1151-1158
64. Abe K, Shimokawa H, Morikawa K, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004;94:385-393
65. Ishikura K, Yamada N, Ito M, et al. Beneficial acute effects of Rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J 2006;70:174-178
66. McNamara PJ, Murthy P, Kantores C, et al. Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide. Am J Physiol Lung Cell Mol Physiol 2008;294:L205-213
67. Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005;91:391-392
68. Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 2002;166:1403-1408
69. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998;273:24266-24271
70. Dichtl W, Dulak J, Frick M, et al. HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2003;23:58-63
71. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98:322-334
72. Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 2003;108:1640-1645
73. Xing XQ, Gan Y, Wu SJ, et al. Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway. Med Hypotheses 2007;68:1108-1113
74. Girgis RE, Li D, Zhan X, et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 2003;285:H938-945
75. Lee JH, Lee DS, Kim EK, et al. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med 2005;172:987-993
76. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2006;291:L668-676
77. Sun X, Ku DD. Rosuvastatin provides pleiotropic protection against pulmonary hypertension, right ventricular hypertrophy, and coronary endothelial dysfunction in rats. Am J Physiol Heart Circ Physiol 2008;294:H801-809
78. Satoh K, Fukumoto Y, Nakano M, et al. Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res 2009;81:226-234
79. Carlin CM, Peacock AJ, Welsh DJ. Fluvastatin inhibits hypoxic proliferation and p38 MAPK activity in pulmonary artery fibroblasts. Am J Respir Cell Mol Biol 2007;37:447-456
80. Brown WV. Hydroxymethylglutaryl coenzyme a reductase inhibition: fluvastatin, a clinical investigators' update. Introduction. Am J Cardiol 1994;73:1D-2D
81. Murata T, Kinoshita K, Hori M, et al. Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol 2005;25:2335-2342
82. McMurtry MS, Bonnet S, Michelakis ED, et al. Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study. Am J Physiol Lung Cell Mol Physiol 2007;293:L933-940
83. Kao PN. Simvastatin treatment of pulmonary hypertension: an observational case series. Chest 2005;127:1446-1452
84. Lee TM, Chen CC, Shen HN, et al. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (Lond) 2009;116:497-505
85. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science 1970;169:1217-1218
86. Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res 2001;49:27-37
87. Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:1339-1346
88. Vuckovic A, Rondelet B, Brion JP, et al. Expression of vasoactive intestinal peptide and related receptors in overcirculation-induced pulmonary hypertension in piglets. Pediatr Res 2009;66:395-399
89. Hamidi SA, Szema AM, Lyubsky S, et al. Clues to VIP function from knockout mice. Ann NY Acad Sci 2006;1070:5-9
90. Said SI, Hamidi SA, Dickman KG, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation 2007;115:1260-1268
91. Hamidi SA, Szema A, Said SI. A single pathogenetic mechanism for vascular remodeling and inflammation in PAH [abstract 275]. European Respiratory Society Annual Congress; 2008
92. Haydar S, Sarti JF, Grisoni ER. Intravenous vasoactive intestinal polypeptide lowers pulmonary-to-systemic vascular resistance ratio in a neonatal piglet model of pulmonary arterial hypertension. J Pediatr Surg 2007;42:758-764
93. Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J 2008;32:1289-1294
94. Wernig K, Griesbacher M, Andreae F, et al. Depot formulation of vasoactive intestinal peptide by protamine-based biodegradable nanoparticles. J Control Release 2008;130:192-198
95. Quinn DA, Dahlberg CG, Bonventre JP, et al. The role of Na+/H+ exchange and growth factors in pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol 1996;14:139-145
96. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 2000;105:21-34
97. Lepetit H, Eddahibi S, Fadel E, et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 2005;25:834-842
98. Todorovich-Hunter L, Dodo H, Ye C, et al. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis 1992;146:213-223
99. Cowan KN, Heilbut A, Humpl T, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000;6:698-702
100. Vieillard-Baron A, Frisdal E, Eddahibi S, et al. Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 2000;87:418-425
101. Zaidi SH, You XM, Ciura S, et al. Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 2002;105:516-521
102. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;335:609-616
103. Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001;108:1141-1150
104. Guignabert C, Raffestin B, Benferhat R, et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 2005;111:2812-2819
105. MacLean MR, Herve P, Eddahibi S, et al. 5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol 2000;131:161-168
106. Rondelet B, Van Beneden R, Kerbaul F, et al. Expression of the serotonin 1b receptor in experimental pulmonary hypertension. Eur Respir J 2003;22:408-412
107. Guignabert C, Izikki M, Tu LI, et al. Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res 2006;98:1323-1330
108. Eddahibi S, Hanoun N, Lanfumey L, et al. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000;105:1555-1562
109. Keegan A, Morecroft I, Smillie D, et al. Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935. Circ Res 2001;89:1231-1239
110. Marcos E, Adnot S, Pham MH, et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med 2003;168:487-493
111. Hironaka E, Hongo M, Sakai A, et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003;60:692-699
112. Kawut SM, Horn EM, Berekashvili KK, et al. Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulm Pharmacol Ther 2006;19:370-374
113. Domenighetti G, Leuenberger P, Feihl F. Haemodynamic effects of ketanserin either alone or with oxygen in COPD patients with secondary pulmonary hypertension. Monaldi Arch Chest Dis 1997;52:429-433
114. Morecroft I, Heeley RP, Prentice HM, et al. 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol 1999;128:730-734
115. Vizza CD, Letizia C, Sciomer S, et al. Increased plasma levels of adrenomedullin, a vasoactive peptide, in patients with end-stage pulmonary disease. Regul Pept 2005;124:187-193
116. Kakishita M, Nishikimi T, Okano Y, et al. Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin Sci (Lond) 1999;96:33-39
117. Nagaya N, Nishikimi T, Uematsu M, et al. Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart 2000;84:653-658
118. Nagaya N, Okumura H, Uematsu M, et al. Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats. Am J Physiol Heart Circ Physiol 2003;285:H2125-2131
119. Qi JG, Ding YG, Tang CS, et al. Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats. Peptides 2007;28:910-919
120. Harada-Shiba M, Takamisawa I, Miyata K, et al. Intratracheal gene transfer of adrenomedullin using polyplex nanomicelles attenuates monocrotaline-induced pulmonary hypertension in rats. Mol Ther 2009;17:1180-1186
121. Nagaya N, Kyotani S, Uematsu M, et al. Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation 2004;109:351-356
122. Smadja DM, Gaussem P, Mauge L, et al. Circulating endothelial cells: a new candidate biomarker of irreversible pulmonary hypertension secondary to congenital heart disease. Circulation 2009;119:374-381
123. Toshner M, Voswinckel R, Southwood M, et al. Evidence for dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med 2009;180:780-787
124. Fadini GP, Schiavon M, Rea F, et al. Depletion of endothelial progenitor cells may link pulmonary fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2007;176:724-725 (Pubitemid 47503082)
125. Junhui Z, Xingxiang W, Guosheng F, et al. Reduced number and activity of circulating endothelial progenitor cells in patients with idiopathic pulmonary arterial hypertension. Respir Med 2008;102:1073-1079
126. Nagaya N, Kangawa K, Kanda M, et al. Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation 2003;108:889-895
127. Takemiya K, Kai H, Yasukawa H, et al. Mesenchymal stem cell-based prostacyclin synthase gene therapy for pulmonary hypertension rats. Basic Res Cardiol 2009;105:403-417
128. Raoul W, Wagner-Ballon O, Saber G, et al. Effects of bone marrow-derived cells on monocrotaline-and hypoxia-induced pulmonary hypertension in mice. Respir Res 2007;8:8
129. Takahashi M, Nakamura T, Toba T, et al. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng 2004;10:771-779
130. Zhao YD, Courtman DW, Deng Y, et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 2005;96:442-450
131. Umar S, de Visser YP, Steendijk P, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension. Am J Physiol Heart Circ Physiol 2009;297:H1606-1616
132. Campbell AI, Kuliszewski MA, Stewart DJ. Cell-based gene transfer to the pulmonary vasculature: endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension. Am J Respir Cell Mol Biol 1999;21:567-575
133. Campbell AI, Zhao Y, Sandhu R, et al. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 2001;104:2242-2248
134. Zhao YD, Campbell AI, Robb M, et al. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res 2003;92:984-991
135. Wang XX, Zhang FR, Shang YP, et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007;49:1566-1571
136. Grigg A, Buchanan M, Whitford H. Late-onset pulmonary arterial hypertension in association with graft-versus-host disease after allogeneic stem-cell transplantation. Am J Hematol 2005;80:38-42
137. Steward CG, Pellier I, Mahajan A, et al. Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis. Br J Haematol 2004;124:63-71
138. Dorfmuller P, Perros F, Balabanian K, et al. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358-363
139. Lee SD, Shroyer KR, Markham NE, et al. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927-934
140. Nicolls MR, Taraseviciene-Stewart L, Rai PR, et al. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 2005;26:1110-1118
141. Cool CD, Stewart JS, Werahera P, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 1999;155:411-419
142. Perros F, Dorfmuller P, Souza R, et al. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 2007;29:462-468
143. Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275-285
144. Isern RA, Yaneva M, Weiner E, et al. Autoantibodies in patients with primary pulmonary hypertension: association with anti-Ku. Am J Med 1992;93:307-312
145. Tamby MC, Chanseaud Y, Humbert M, et al. Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005;60:765-772
146. Tamby MC, Humbert M, Guilpain P, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J 2006;28:799-807 (Pubitemid 46332002)
147. Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628-1631
148. Sanchez O, Marcos E, Perros F, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007;176:1041-1047
149. Balabanian K, Foussat A, Dorfmuller P, et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:1419-1425
150. Fartoukh M, Emilie D, Le Gall C, et al. Chemokine macrophage inflammatory protein-1alpha mRNA expression in lung biopsy specimens of primary pulmonary hypertension. Chest 1998;114:50S-1S
151. Quarck R, Nawrot T, Meyns B, et al. C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol 2009;53:1211-1218
152. Perros F, Dorfmuller P, Souza R, et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 2007;29:937-943
153. Voelkel NF, Tuder RM, Bridges J, et al. Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol 1994;11:664-675
154. Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 2009;10:6
155. Wang GS, Qian GS, Mao BL, et al. Changes of interleukin-6 and Janus kinases in rats with hypoxic pulmonary hypertension. Zhonghua Jie He He Hu Xi Za Zhi 2003;26:664-667
156. Golembeski SM, West J, Tada Y, et al. Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest 2005;128:572S-3S
157. Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009;104:236-244, 228p following 244
158. Ikeda Y, Yonemitsu Y, Kataoka C, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 2002;283:H2021-2028
159. Nishimura T, Faul JL, Berry GJ, et al. 40-O-(2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 2001;163:498-502
160. Zhou H, Liu H, Porvasnik SL, et al. Heme oxygenase-1 mediates the protective effects of rapamycin in monocrotaline-induced pulmonary hypertension. Lab Invest 2006;86:62-71
161. Schermuly RT, Pullamsetti SS, Kwapiszewska G, et al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation 2007;115:2331-2339
162. Wei L, Liu T, Liu B, et al. Effect of triptolide on the development of monocrotaline-induced pulmonary hypertension in pneumonectomized rat. Sichuan Da Xue Xue Bao Yi Xue Ban 2007;38:806-809
163. Tofovic SP, Salah EM, Mady HH, et al. Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2005;46:430-437
164. Gui Y, Zheng XL. 2-methoxyestradiol induces cell cycle arrest and mitotic cell apoptosis in human vascular smooth muscle cells. Hypertension 2006;47:271-280
165. Ogawa A, Nakamura K, Matsubara H, et al. Prednisolone inhibits proliferation of cultured pulmonary artery smooth muscle cells of patients with idiopathic pulmonary arterial hypertension. Circulation 2005;112:1806-1812
166. Csiszar A, Labinskyy N, Olson S, et al. Resveratrol prevents monocrotaline-induced pulmonary hypertension in rats. Hypertension 2009;54:668-675
167. Sanchez O, Sitbon O, Jais X, et al. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006;130:182-189
168. Bellotto F, Chiavacci P, Laveder F, et al. Effective immunosuppressive therapy in a patient with primary pulmonary hypertension. Thorax 1999;54:372-374
169. Sanchez O, Humbert M, Sitbon O, et al. Treatment of pulmonary hypertension secondary to connective tissue diseases. Thorax 1999;54:273-277
170. Sun CK, Lee FY, Sheu JJ, et al. Early combined treatment with cilostazol and bone marrow-derived endothelial progenitor cells markedly attenuates pulmonary arterial hypertension in rats. J Pharmacol Exp Ther 2009;330:718-726
171. Tawara S, Fukumoto Y, Shimokawa H. Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2007;50:195-200 (Pubitemid 47267745)
172. Jiang BH, Tawara S, Abe K, et al. Acute vasodilator effect of fasudil, a
173. Satoh M, Satoh A. 3-Hydroxy-3-methylglutaryl (HMG)-COA reductase inhibitors and phosphodiesterase type V inhibitors attenuate right ventricular pressure and remodeling in a rat model of pulmonary hypertension. J Pharm Pharm Sci 2008;11:118s-30s
174. Zhao L, Sebkhi A, Ali O, et al. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Respir J 2009;34:948-957
175. Voswinckel R, Ziegelhoeffer T, Heil M, et al. Circulating vascular progenitor cells do not contribute to compensatory lung growth. Circ Res 2003;93:372-379
176. Oka M, Homma N, Taraseviciene-Stewart L, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007;100:923-929
177. Nagaoka T, Gebb SA, Karoor V, et al. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 2006;100:996-1002
178. Liu B, Wang XQ, Yu L, et al. Simvastatin restores down-regulated GATA-6 expression in pulmonary hypertensive rats. Exp Lung Res 2009;35:411-426
179. Said SI. The vasoactive intestinal peptide gene is a key modulator of pulmonary vascular remodeling and inflammation. Ann NY Acad Sci 2008;1144:148-153