Novel Targets of Drug Treatment for Pulmonary Hypertension

American Journal of Cardiovascular Drugs

Volumn 15, Issue 4, 2015, Pages 225-234

  Hu, Jian ^a   Xu, Qinzi ^a   McTiernan, Charles ^a   Lai, Yen Chun ^a   Osei Hwedieh, David ^a   Gladwin, Mark ^a,b  

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIHYPERTENSIVE AGENT; AT 877ER; BARDOXOLONE METHYL; CHEMOKINE RECEPTOR CCR5; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; FLUOXETINE; G PROTEIN COUPLED RECEPTOR; GROWTH FACTOR; IMATINIB; MICRORNA; NILOTINIB; PAROXETINE; PHOSPHOTRANSFERASE; RHO KINASE INHIBITOR; RITUXIMAB; SEROTONIN UPTAKE INHIBITOR; SERTRALINE; SORAFENIB; TACROLIMUS; UNCLASSIFIED DRUG; VASOACTIVE INTESTINAL POLYPEPTIDE; WNT PROTEIN; IMMUNOSUPPRESSIVE AGENT; PROTEIN KINASE INHIBITOR;

APOPTOSIS; ARTICLE; BLOOD VESSEL WALL; CELL PROLIFERATION; CONCEPTUAL FRAMEWORK; CONTROLLED CLINICAL TRIAL (TOPIC); ENDOTHELIAL PROGENITOR CELL; ENDOTHELIUM CELL; HUMAN; IMMUNITY; INFLAMMATION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PRIORITY JOURNAL; PULMONARY ARTERY SMOOTH MUSCLE CELL; PULMONARY HYPERTENSION; SIGNAL TRANSDUCTION; CLASSIFICATION; CLINICAL TRIAL (TOPIC); DRUG EFFECTS; EXPERIMENTAL THERAPY; HYPERTENSION, PULMONARY; METABOLISM; PATHOLOGY; PHYSIOLOGY; PROCEDURES; PULMONARY ARTERY; SMOOTH MUSCLE CELL; VASCULAR REMODELING;

CLINICAL TRIALS AS TOPIC; ENDOTHELIAL PROGENITOR CELLS; HUMANS; HYPERTENSION, PULMONARY; IMMUNOSUPPRESSIVE AGENTS; MICRORNAS; MYOCYTES, SMOOTH MUSCLE; PROTEIN KINASE INHIBITORS; PULMONARY ARTERY; SEROTONIN UPTAKE INHIBITORS; SIGNAL TRANSDUCTION; THERAPIES, INVESTIGATIONAL; VASCULAR REMODELING;

EID: 84937973274     PISSN: 11753277     EISSN: 1179187X     Source Type: Journal    
DOI: 10.1007/s40256-015-0125-4     Document Type: Article

References (144)

1. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219–63.
2. Pullamsetti SS, Schermuly R, Ghofrani A, et al. Novel and emerging therapies for pulmonary hypertension. Am J Respir Crit Care Med. 2014;189(4):394–400.
3. George MG, Schieb LJ, Ayala C, et al. Pulmonary hypertension surveillance. Chest. 2014;146(2):476–95.
4. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115(5):343–9.
5. Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811–21.
6. Perros F, Montani D, Dorfmu¨ller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:81–8.
7. Nakamura K, Akagi S, Ogawa A, et al. Pro-apoptotic effects of imatinib on PDGF stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Int J Cardiol. 2011;159(2):100–6.
8. Vantler M, Karikkineth BC, Naito H, et al. PDGF-BB protects cardiomyocytes from apoptosis and improves contractile function of engineered heart tissue. J Mol Cell Cardiol. 2010;48:1316–23.
9. Panky EA, Thammasiboon S, Lasker GF, et al. Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat. Am J Physiol Heart Circ Physiol. 2013;305:H1288–96.
10. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med. 2005;353:1412–3.
11. Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006;145:152–3.
12. Souza R, Sitbon O, Parent G, et al. Long term imatinib treatment in pulmonary arterial hypertension. Thorax. 2006;61:736.
13. Ten Freyhaus H, Dumitrescu D, Bovenschulte H, et al. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension. Clin Res Cardiol. 2009;98:265–7.
14. Tapper EB, Knowles D, Heffron T, et al. Portopulmonary hypertension: imatinib is a novel treatment and the Emory experience with this condition. Transplant Proc. 2009;41:1969–71.
15. Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182:1171–7.
16. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–38.
17. Maurer B, Reich N, Juengel A, et al. Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Ann Rheum Dis. 2012;71(8):1382–7.
18. Efficacy, safety, tolerability and pharmocokinetics (PK) of nilotinib (AMN107) in pulmonary arterial hypertension (PAH). Novartis Pharmaceuticals. https://clinicaltrials.gov/show/NCT01179737. Accessed April 2014.
19. 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(2):278–91.
20. Gomberg-Maitland M, Maitland ML, Barst RJ, et al. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2010;87(3):303–10.
21. Taçoy G, Çengel A, Özkurt ZN, et al. Dasatinib-induced pulmonary hypertension in acute lymphoblastic leukemia: case report. Turk Kardiyol Dern Ars. 2015;43(1):78–81.
22. Hong JH, Lee SE, Choi SY, et al. Reversible pulmonary arterial hypertension associated with dasatinib for chronic myeloid leukemia. Cancer Res Treat. 2014;17:1–6.
23. Buchelli Ramirez HL, Álvarez Álvarez CM, Rodríguez Reguero JJ, et al. Reversible pre-capillary pulmonary hypertension due to dasatinib. Respir Care. 2014;59:e77–80.
24. Ciuclan L, Bonneau O, Hussey M, et al. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2011;184(10):1171–82.
25. Robertson TP, Dipp M, Ward JP, et al. Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat. Br J Pharmacol. 2000;131(1):5–9.
26. Hu J, Tarantelli R, Simon M, et al. Simian immunodeficiency virus induces pulmonary arterial hypertension in rhesus macaques: a hemodynamic study. Circulation. 2013;128(22):A18705.
27. Robertson TP, Aaronson PI, Ward JP. Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent. Am J Physiol Lung Cell Mol Physiol. 2003;284(6):L1121–6.
28. Wang Z, Lanner MC, Jin N, et al. Hypoxia inhibits myosin phosphatase in pulmonary arterial smooth muscle cells: role of Rho-kinase. Am J Respir Cell Mol Biol. 2003;29(4):465–71.
29. 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(3):385–93.
30. Abe K, Tawara S, Oi K, et al. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol. 2006;48(6):280–5.
31. Li F, Xia W, Li A, et al. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol Res. 2007;55(1):64–71.
32. Hisaoka T, Yano M, Ohkusa T, et al. Enhancement of Rho/Rho-kinase system in regulation of vascular smooth muscle contraction in tachycardia-induced heart failure. Cardiovasc Res. 2001;49(2):319–29.
33. Yamashita K, Kotani Y, Nakajima Y, et al. Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons. Brain Res. 2007;1154:215–24.
34. 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(3):391–2.
35. 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(2):174–8.
36. Fujita H, Fukumoto Y, Saji K, et al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels. 2010;25(2):144–9.
37. Kojonazarov B, Myrzaakhmatova A, Sooronbaev T, et al. Effects of Fasudil in patients with high-altitude pulmonary hypertension. Eur Respir J. 2012;39(2):496–8.
38. Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389(6654):990–4.
39. Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clinical trial with a Rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013;77(10):2619–25.
40. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169:1217–8.
41. Maruno K, Absood A, Said SI. VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells. Am J Physiol. 1995;268:L1047–51.
42. Saga T, Said SI. Vasoactive intestinal peptide relaxes isolated strips of human bronchus, pulmonary artery, and lung parenchyma. Trans Assoc Am Physicians. 1984;97:304–10.
43. Hu J, Sharifi-Sanjani M, Shiva S, et al. Nitrite prevents right ventricular failure and remodeling induced by pulmonary artery banding. Circulation. 2013;128(22):A16923.
44. Nandiwada PA, Kadowitz PJ, Said SI, et al. Pulmonary vasodilator responses to vasoactive intestinal peptide in the cat. J Appl Physiol. 1985;58(5):1723–8.
45. Hashimoto H, Negishi M, Ichikawa A. Identification of a prostacyclin receptor coupled to the adenylate cyclase system via a stimulatory GTP-binding protein in mouse mastocytoma P-815 cells. Prostaglandins. 1990;40(5):491–505.
46. Said SI, Hamidi SA, Dickman KG, et al. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation. 2007;115:1260–8.
47. 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;42:758–64.
48. Said SI, Hamidi SA. Pharmacogenomics in pulmonary arterial hypertension: toward a mechanistic, target-based approach to therapy. Pulm Circ. 2011;1(3):383–8.
49. 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;111:1339–46.
50. Leuchte HH, Baezner C, Baumgartner RA, et al. Inhalation of vasoactive intestinal peptide in pulmonary hypertension. Eur Respir J. 2008;32(5):1289–94.
51. Hamidi SA, Lin RZ, Szema AM, et al. VIP and endothelin receptor antagonist: an effective combination against experimental pulmonary arterial hypertension. Respir Res. 2011;12:141.
52. Dempsie Y, MacLean MR. Pulmonary hypertension: therapeutic targets within the serotonin system. Br J Pharmacol. 2008;155:455–62.
53. Eddahibi S, Adnot S. The serotonin pathway in pulmonary hypertension. Arch Mal Coeur Vaiss. 2006;99:621–5.
54. Eddahibi S, Raffestin B, Hamon M, et al. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? J Lab Clin Med. 2002;139:194–201.
55. Eddahibi S, Raffestin B, Pham I, et al. Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol. 1997;272(3 Pt 2):H1173–81.
56. Guibert C, Marthan R, Savineau JP. 5-HT induces an arachidonic acid-sensitive calcium influx in rat small intrapulmonary artery. Am J Physiol Lung Cell Mol Physiol. 2004;286(6):L1228–36.
57. Liu JQ, Folz RJ. Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction. Am J Physiol Lung Cell Mol Physiol. 2004;287:L111–8.
58. Deuchar GA, Hicks MN, MacLean MR. The role of 5-hydroxytryptamine in the control of pulmonary vascular tone in a rabbit model of pulmonary hypertension secondary to left ventricular dysfunction. Pulm Pharmacol Ther. 2005;18(1):23–31.
59. 2A receptors involved in the pulmonary artery remodeling of pulmonary artery hypertension. Exp Lung Res. 2013;39(2):70–9.
60. Liu DB, Hu J, Zhang MK, et al. Low-dose ketamine combined with pentobarbital in a miniature porcine model for a cardiopulmonary bypass procedure: a randomized controlled study. Eur J Anaesthesiol. 2009;26(5):389–95.
61. Vane J, Corin RE. Prostacyclin: a vascular mediator. Eur J Vasc Endovasc Surg. 2003;26(6):571–8.
62. Morecroft I, Loughlin L, Nilsen M, et al. Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther. 2005;313(2):539–48.
63. Guignabert C, Raffestin B, Benferhat R, et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation. 2005;111:2812–9.
64. Lushaj EB, Hu J, Haworth R, et al. Intravital microscopy to study myocardial engraftment. Interact CardioVasc Thorac Surg. 2012;15(1):5–9.
65. 1B receptor/SERT antagonist in experimental pulmonary hypertension. Cardiovasc Res. 2010;85(3):593–603.
66. Marcos E, Adnot S, Pham MH, et al. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med. 2003;168:487–93.
67. Zhu SP, Mao ZF, Huang J, et al. Continuous fluoxetine administration prevents recurrence of pulmonary arterial hypertension and prolongs survival in rats. Clin Exp Pharmacol Physiol. 2009;36:e1–5.
68. Shah SJ, Gomberg-Maitland M, Thenappan T, et al. Selective serotonin reuptake inhibitors and the incidence and outcome of pulmonary hypertension. Chest. 2009;136(3):694–700.
69. Kawut SM, Horn EM, Berekashvili KK, et al. Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulm Pharmacol Ther. 2006;19(5):370–4.
70. Dhalla IA, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and pulmonary arterial hypertension: a case–control study. Chest. 2012;141(2):348–53.
71. Sadoughi A, Roberts KE, Preston IR, et al. Use of selective serotonin reuptake inhibitors and outcomes in pulmonary arterial hypertension. Chest. 2013;144(2):531–41.
72. Lin RZ, Dreyzin A, Aamodt K, et al. Functional endothelial progenitor cells from cryopreserved umbilical cord blood. Cell Transplant. 2011;20(4):515–22.
73. Ormiston ML, Deng Y, Stewart DJ, et al. Innate immunity in the therapeutic actions of endothelial progenitor cells in pulmonary hypertension. Am J Respir Cell Mol Biol. 2010;43(5):546–54.
74. Vanneaux V, El-Ayoubi F, Delmau C, et al. In vitro and in vivo analysis of endothelial progenitor cells from cryopreserved umbilical cord blood: are we ready for clinical application? Cell Transplant. 2010;19(9):1143–55.
75. Lozonschi L, Bombien R, Osaki S, et al. Transapical mitral valved stent implantation: a survival series in swine. J Thorac Cardiovasc Surg. 2010;140(2):422–6.
76. 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(14):1566–71.
77. Yip HK, Chang LT, Sun CK, et al. Autologous transplantation of bone marrow-derived endothelial progenitor cells attenuates monocrotaline-induced pulmonary arterial hypertension in rats. Crit Care Med. 2008;36(3):873–80.
78. 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(4):442–50.
79. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.
80. Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95(3):952–8.
81. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95(4):343–53.
82. Ding DC, Shyu WC, Lin SZ, et al. The role of endothelial progenitor cells in ischemic cerebral and heart diseases. Cell Transplant. 2007;16(3):273–84.
83. Marsboom G, Janssens S. Endothelial progenitor cells: new perspectives and applications in cardiovascular therapies. Expert Rev Cardiovasc Ther. 2008;6(5):687–701.
84. Diller GP, van Eijl S, Okonko DO, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation. 2008;117(23):3020–30.
85. 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(7):724–5.
86. 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(7):1073–9.
87. Asosingh K, Aldred MA, Vasanji A, et al. Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am J Pathol. 2008;172(3):615–27.
88. Marsboom G, Pokreisz P, Gheysens O, et al. Sustained endothelial progenitor cell dysfunction after chronic hypoxia-induced pulmonary hypertension. Stem Cells. 2008;26(4):1017–26.
89. Toshner M, Voswinckel R, Southwood M, et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2009;180(8):780–7.
90. Takahashi M, Nakamura T, Toba T. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs. Tissue Eng. 2004;10(5–6):771–9.
91. Xia L, Fu GS, Yang JX, et al. Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension. Cytotherapy. 2009;11(4):492–502.
92. 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;108:889–95.
93. Wei L, Zhu W, Xia L, et al. Therapeutic effect of eNOS-transfected endothelial progenitor cells on hemodynamic pulmonary arterial hypertension. Hypertens Res. 2013;36:414–21.
94. Diller GP, van Eijl S, Okonko DO, et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation. 2008;117:3020–30.
95. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348(7):593–600.
96. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999;18(14):3964–72.
97. Werner N, Junk S, Laufs U, et al. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res. 2003;93(2):e17–24.
98. Rehman J. Feeling the elephant of cardiovascular cell therapy. Circulation. 2010;121(2):197–9.
99. Gnecchi M, Zhang Z, Ni A, et al. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103(11):1204–19.
100. Santhanam AV, Smith LA, He T, et al. Endothelial progenitor cells stimulate cerebrovascular production of prostacyclin by paracrine activation of cyclooxygenase-2. Circ Res. 2007;100(9):1379–88.
101. Urbich C, Aicher A, Heeschen C, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005;39(5):733–42.
102. Zhu JH, Wang XX, Zhang FR, et al. Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: open-label pilot study. Pediatr Transplant. 2008;12(6):650–5.
103. Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007;109:1801–9.
104. Hirschi KK, Ingram DA, Yoder MC. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol. 2008;28:1584–95.
105. Baker CD, Seedorf GJ, Wisniewski BL, et al. Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2013;305(1):L73–81.
106. Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72.
107. Tamosiuniene R, Tian W, Dhillon G, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res. 2011;109:867–79.
108. Rabinovitch M, Guignabert C, Humbert M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115:165–75.
109. Meloche J, Renard S, Provencher S, et al. Anti-inflammatory and immunosuppressive agents in PAH. Handb Exp Pharmacol. 2013;218:437–76.
110. Kim YM, Haghighat L, Spiekerkoetter E, et al. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol. 2011;179(3):1560–72.
111. Bardoxolone methyl evaluation in patients with pulmonary arterial hypertension (PAH)—LARIAT. Reata Pharmaceuticals. http://clinicaltrials.gov/ct2/show/NCT02036970. Accessed May 2015.
112. Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013;123:3600–13.
113. Spiekerkoetter E, Zamanian R. FK506 (Tacrolimus) in pulmonary arterial hypertension (TransformPAH). http://clinicaltrials.gov/ct2/show/NCT01647945. Accessed May 2015.
114. Nicolls M, Badesch DB, Medsger TA. Rituximab for treatment of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). http://clinicaltrials.gov/ct2/show/NCT01086540. Accessed May 2015.
115. Amsellem V, Lipskaia L, Abid S, et al. CCR5 as a treatment target in pulmonary arterial hypertension. Circulation. 2014;130(11):880–91.
116. Lutter G, Quaden R, Osaki S, et al. Off-pump transapical mitral valve replacement. Eur J Cardiothorac Surg. 2009;36(1):124–8.
117. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006;354:610–21.
118. Schecter AD, Calderon TM, Berman AB, et al. Human vascular smooth muscle cells possess functional CCR5. J Biol Chem. 2000;275:5466–71.
119. Ishida Y, Kimura A, Kuninaka Y, et al. Pivotal role of the CCL5/CCR5 interaction for recruitment of endothelial progenitor cells in mouse wound healing. J Clin Invest. 2012;122:711–21.
120. Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996;381:667–73.
121. Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996;381:661–6.
122. Combadiere C, Potteaux S, Rodero M, et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117:1649–57.
123. Papkoff J, Rubinfeld B, Schryver B, et al. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol. 1996;16:2128–34.
124. Shulman JM, Perrimon N, Axelrod JD, et al. Frizzled signaling and the developmental control of cell polarity. Trends Genet. 1998;14:452–8.
125. Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell. 2003;5:367–77.
126. Laumanns IP, Fink L, Wilhelm J, et al. The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2009;40:683–91.
127. de Jesus Perez VA, Alastalo TP, Wu JC, et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J Cell Biol. 2009;184:83–99.
128. Yu XM, Wang L, JF Li, et al. Wnt5a inhibits hypoxia-induced pulmonary arterial smooth muscle cell proliferation by downregulation of β-catenin. Am J Physiol Lung Cell Mol Physiol. 2013;304:L103–11.
129. Laumanns IP, Fink L, Wilhelm J, et al. The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2009;40(6):683–91.
130. Lin C, Lu W, Zhai L, et al. Mesd is a general inhibitor of different Wnt ligands in Wnt/LRP signaling and inhibits PC-3 tumor growth in vivo. FEBS Lett. 2011;585(19):3120–5.
131. Alapati D, Rong M, Chen S, et al. Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats. Pediatr Res. 2013;73(6):719–25.
132. Alapati D, Rong M, Chen S, et al. Inhibition of β-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Respir Cell Mol Biol. 2014;51:104–13.
133. West JD, Austin ED, Gaskill C, et al. Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2014;307:C415–30.
134. Farh KK, Grimson A, Jan C, et al. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science. 2005;310:1817–21.
135. Voelkel NF, Cool C, Lee SD, et al. Primary pulmonary hypertension between inflammation and cancer. Chest. 1998;114(3 Suppl.):225S–30S.
136. Paulin R, Courboulin A, Barrier M, et al. From oncoproteins/tumor suppressors to microRNAs, the newest therapeutic targets for pulmonary arterial hypertension. J Mol Med. 2011;89:1089–101.
137. Drake JI, Bogaard HJ, Mizuno S, et al. Molecular signature of a right heart failure program in chronic severe pulmonary hypertension. Am J Respir Cell Mol Biol. 2011;45:1239–47.
138. McDonald RA, Hata A, MacLean MR, et al. MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodeling. Cardiovasc Res. 2012;93:594–604.
139. Courboulin A, Paulin R, Giguère NJ, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208:535–48.
140. Kim J, Kang Y, Kojima Y, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013;19:74–82.
141. Caruso P, MacLean MR, Khanin R, et al. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol. 2010;30:716–23.
142. Pullamsetti SS, Doebele C, Fischer A, et al. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2012;185:409–19.
143. Bouchie A. First microRNA mimic enters clinic. Nat Biotechnol. 2013;31:577.
144. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368:1685–94.