Key role of the RhoA/Rho kinase system in pulmonary hypertension

Pulmonary Pharmacology and Therapeutics

Volumn 24, Issue 1, 2011, Pages 1-14

  Connolly, Michelle J ^a   Aaronson, Philip I ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Chronic hypoxia; Fasudil; Monocrotaline; Pulmonary arterial hypertension; Pulmonary hypertension; Rho kinase

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; ALPHA SMOOTH MUSCLE ACTIN; CALCIUM ION; CALPONIN; ENDOTHELIN 1; FASUDIL; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; RHO KINASE; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; SEROTONIN; TRANSGELIN;

APOPTOSIS; BLOOD VESSEL FUNCTION; CALCIUM HOMEOSTASIS; CELL MOTILITY; CELL PROLIFERATION; DRUG MECHANISM; ENZYME ACTIVATION; HUMAN; HYPOXIA; INFLAMMATION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PULMONARY HYPERTENSION; RECEPTOR UPREGULATION; REVIEW; SMOOTH MUSCLE FIBER;

ANIMALS; ANOXIA; BONE MORPHOGENETIC PROTEIN RECEPTORS, TYPE II; CELL PROLIFERATION; ENDOTHELIN-1; HUMANS; HYPERTENSION, PULMONARY; MUSCLE, SMOOTH, VASCULAR; NFATC TRANSCRIPTION FACTORS; RHO-ASSOCIATED KINASES; RHOA GTP-BINDING PROTEIN; SEROTONIN; VASOCONSTRICTION;

EID: 79251600675     PISSN: 10945539     EISSN: 15229629     Source Type: Journal    
DOI: 10.1016/j.pupt.2010.09.001     Document Type: Review

References (219)

1. Humbert M., Sitbon O., Chaouat A., Bertocchi M., Habib G., Gressin V., et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006, 173(9):1023-1030.
2. Simonneau G., Robbins I.M., Beghetti M., Channick R.N., Delcroix M., Denton C.P., et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009, 54(Suppl. 1):S43-S54.
3. Stenmark K.R., Meyrick B., Galie N., Mooi W.J., McMurtry I.F. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009, 297(6):L1013-L1032.
4. Han M.K., McLaughlin V.V., Criner G.J., Martinez F.J. Pulmonary diseases and the heart. Circulation 2007, 116(25):2992-3005.
5. Barbera J.A., Peinado V.I., Santos S. Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J 2003, 21(5):892-905.
6. Chaouat A., Naeije R., Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008, 32(5):1371-1385.
7. Boutin-Forzano S., Moreau D., Kalaboka S., Gay E., Bonnefoy X., Carrozzi L., et al. Reported prevalence and co-morbidity of asthma, chronic bronchitis and emphysema: a pan-European estimation. Int J Tuberc Lung Dis 2007, 11(6):695-702.
8. Rai P.R., Cool C.D., King J.A., Stevens T., Burns N., Winn R.A., et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2008, 178(6):558-564.
9. Kitazawa T., Masuo M., Somlyo A.P. G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc Natl Acad Sci U S A 1991, 88(20):9307-9310.
10. Ichikawa K., Ito M., Hartshorne D.J. Phosphorylation of the large subunit of myosin phosphatase and inhibition of phosphatase activity. J Biol Chem 1996, 271(9):4733-4740.
11. Uehata M., Ishizaki T., Satoh H., Ono T., Kawahara T., Morishita T., et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997, 389(6654):990-994.
12. Vicari R.M., Chaitman B., Keefe D., Smith W.B., Chrysant S.G., Tonkon M.J., et al. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J Am Coll Cardiol 2005, 46(10):1803-1811.
13. Alessi D., MacDougall L.K., Sola M.M., Ikebe M., Cohen P. The control of protein phosphatase-1 by targetting subunits. The major myosin phosphatase in avian smooth muscle is a novel form of protein phosphatase-1. Eur J Biochem 1992, 210(3):1023-1035.
14. 2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 2003, 83(4):1325-1358.
15. Lederer D.J., Horn E.M., Rosenzweig E.B., Karmally W., Jahnes M., Barst R.J., et al. Plasma serotonin levels are normal in pulmonary arterial hypertension. Pulm Pharmacol Ther 2008, 21(1):112-114.
16. 2+-dependent activation of Rho and Rho kinase in membrane depolarization-induced and receptor stimulation-induced vascular smooth muscle contraction. Circ Res 2003, 93(6):548-556.
17. Hall A. Rho GTPases and the actin cytoskeleton. Science 1998, 279(5350):509-514.
18. Kaibuchi K., Kuroda S., Amano M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu Rev Biochem 1999, 68:459-486.
19. Leung T., Manser E., Tan L., Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem 1995, 270(49):29051-29054.
20. Leung T., Chen X.Q., Manser E., Lim L. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 1996, 16(10):5313-5327.
21. 2+ sensitization of smooth muscle contraction through activation of Rho-kinase. Pflugers Arch 2001, 441(5):596-603.
22. 2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C. Circ Res 2002, 91(2):112-119.
23. Fukata Y., Amano M., Kaibuchi K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 2001, 22(1):32-39.
24. Fukumoto Y., Kaibuchi K., Hori Y., Fujioka H., Araki S., Ueda T., et al. Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. Oncogene 1990, 5(9):1321-1328.
25. Ueda T., Kikuchi A., Ohga N., Yamamoto J., Takai Y. Purification and characterization from bovine brain cytosol of a novel regulatory protein inhibiting the dissociation of GDP from and the subsequent binding of GTP to rhoB p20, a ras p21-like GTP-binding protein. J Biol Chem 1990, 265(16):9373-9380.
26. Sawada N., Itoh H., Yamashita J., Doi K., Inoue M., Masatsugu K., et al. cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun 2001, 280(3):798-805.
27. Seto M., Yano K., Sasaki Y., Azuma H. Intimal hyperplasia enhances myosin phosphorylation in rabbit carotid artery. Exp Mol Pathol 1993, 58(1):1-13.
28. Harada T., Seto M., Sasaki Y., London S., Luo Z., Mayberg M. The time course of myosin light-chain phosphorylation in blood-induced vasospasm. Neurosurgery 1995, 36(6):1178-1182.
29. Katsumata N., Shimokawa H., Seto M., Kozai T., Yamawaki T., Kuwata K., et al. Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta. Circulation 1997, 96(12):4357-4363.
30. Shimokawa H., Seto M., Katsumata N., Amano M., Kozai T., Yamawaki T., et al. Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999, 43(4):1029-1039.
31. Wamhoff B.R., Bowles D.K., Owens G.K. Excitation-transcription coupling in arterial smooth muscle. Circ Res 2006, 98(7):868-878.
32. Mack C.P., Somlyo A.V., Hautmann M., Somlyo A.P., Owens G.K. Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization. J Biol Chem 2001, 276(1):341-347.
33. Guilluy C., Eddahibi S., Agard C., Guignabert C., Izikki M., Tu L., et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 2009, 179(12):1151-1158.
34. Coleman M.L., Marshall C.J., Olson M.F. RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol 2004, 5(5):355-366.
35. Welsh C.F., Roovers K., Villanueva J., Liu Y., Schwartz M.A., Assoian R.K. Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nat Cell Biol 2001, 3(11):950-957.
36. Weber J.D., Hu W., Jefcoat S.C., Raben D.M., Baldassare J.J. Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27. J Biol Chem 1997, 272(52):32966-32971.
37. Croft D.R., Olson M.F. The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Mol Cell Biol 2006, 26(12):4612-4627.
38. Sawada N., Itoh H., Ueyama K., Yamashita J., Doi K., Chun T.H., et al. Inhibition of rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation 2000, 101(17):2030-2033.
39. Ohashi K., Hosoya T., Takahashi K., Hing H., Mizuno K. A Drosophila homolog of LIM-kinase phosphorylates cofilin and induces actin cytoskeletal reorganization. Biochem Biophys Res Commun 2000, 276(3):1178-1185.
40. Loirand G., Guerin P., Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006, 98(3):322-334.
41. Li M., Li Z., Sun X. Statins suppress MMP2 secretion via inactivation of RhoA/ROCK pathway in pulmonary vascular smooth muscles cells. Eur J Pharmacol 2008, 591(1-3):219-223.
42. Shi J., Wei L. Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp (Warsz) 2007, 55(2):61-75.
43. Shibata R., Kai H., Seki Y., Kusaba K., Takemiya K., Koga M., et al. Rho-kinase inhibition reduces neointima formation after vascular injury by enhancing Bax expression and apoptosis. J Cardiovasc Pharmacol 2003, 1(Suppl. 42):S43-S47.
44. Liu C., Chen J., Gao Y., Deng B., Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev 2009, 3:CD004434.
45. Galie N., Manes A., Negro L., Palazzini M., Bacchi-Reggiani M.L., Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009, 30(4):394-403.
46. Meyrick B., Reid L. Endothelial and subintimal changes in rat hilar pulmonary artery during recovery from hypoxia. A quantitative ultrastructural study. Lab Invest 1980, 42(6):603-615.
47. Davie N.J., Crossno J.T., Frid M.G., Hofmeister S.E., Reeves J.T., Hyde D.M., et al. Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 2004, 286(4):L668-L678.
48. Frid M.G., Kale V.A., Stenmark K.R. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res 2002, 90(11):1189-1196.
49. Jones P.L., Cowan K.N., Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 1997, 150(4):1349-1360.
50. Hislop A., Reid L. New findings in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. Br J Exp Pathol 1976, 57(5):542-554.
51. Rabinovitch M., Gamble W., Nadas A.S., Miettinen O.S., Reid L. Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. Am J Physiol 1979, 236(6):H818-H827.
52. Partovian C., Adnot S., Raffestin B., Louzier V., Levame M., Mavier I.M., et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2000, 23(6):762-771.
53. Sitbon O., Humbert M., Jais X., Ioos V., Hamid A.M., Provencher S., et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005, 111(23):3105-3111.
54. Roberts D.H., Lepore J.J., Maroo A., Semigran M.J., Ginns L.C. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Chest 2001, 120(5):1547-1555.
55. Taraseviciene-Stewart L., Kasahara Y., Alger L., Hirth P., Mc M.G., Waltenberger J., et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001, 15(2):427-438.
56. Taraseviciene-Stewart L., Scerbavicius R., Choe K.H., Cool C., Wood K., Tuder R.M., et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2006, 291(4):L668-L676.
57. Sakao S., Taraseviciene-Stewart L., Lee J.D., Wood K., Cool C.D., Voelkel N.F. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J 2005, 19(9):1178-1180.
58. Sakao S., Tatsumi K., Voelkel N.F. Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respir Res 2009, 10:95-103.
59. Masri F.A., Xu W., Comhair S.A., Asosingh K., Koo M., Vasanji A., et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007, 293(3):L548-L554.
60. Budhiraja R., Tuder R.M., Hassoun P.M. Endothelial dysfunction in pulmonary hypertension. Circulation 2004, 109(2):159-165.
61. Brett S.J., Simon J., Gibbs R., Pepper J.R., Evans T.W. Impairment of endothelium-dependent pulmonary vasodilation in patients with primary pulmonary hypertension. Thorax 1996, 51(1):89-91.
62. Tuder R.M., Cool C.D., Geraci M.W., Wang J., Abman S.H., Wright L., et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999, 159(6):1925-1932.
63. Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995, 333(4):214-221.
64. Mason N.A., Springall D.R., Burke M., Pollock J., Mikhail G., Yacoub M.H., et al. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol 1998, 185(3):313-318.
65. Welsh C.H., Hassell K.L., Badesch D.B., Kressin D.C., Marlar R.A. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996, 110(3):710-717.
66. Christman B.W., McPherson C.D., Newman J.H., King G.A., Bernard G.R., Groves B.M., et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992, 327(2):70-75.
67. Chaouat A., Weitzenblum E., Higenbottam T. The role of thrombosis in severe pulmonary hypertension. Eur Respir J 1996, 9(2):356-363.
68. Morrell N.W. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling?. Proc Am Thorac Soc 2006, 3(8):680-686.
69. Eickelberg O., Morty R.E. Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. Trends Cardiovasc Med 2007, 17(8):263-269.
70. Davies R.J., Morrell N.W. Molecular mechanisms of pulmonary arterial hypertension: role of mutations in the bone morphogenetic protein type II receptor. Chest 2008, 134(6):1271-1277.
71. Machado R.D., Eickelberg O., Elliott C.G., Geraci M.W., Hanaoka M., Loyd J.E., et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009, 54(Suppl. 1):S32-S42.
72. Machado R.D., Aldred M.A., James V., Harrison R.E., Patel B., Schwalbe E.C., et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006, 27(2):121-132.
73. Yu P.B., Beppu H., Kawai N., Li E., Bloch K.D. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. J Biol Chem 2005, 280(26):24443-24450.
74. Atkinson C., Stewart S., Upton P.D., Machado R., Thomson J.R., Trembath R.C., et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002, 105(14):1672-1678.
75. Dewachter L., Adnot S., Guignabert C., Tu L., Marcos E., Fadel E., et al. Bone morphogenetic protein signaling in heritable versus idiopathic pulmonary hypertension. Eur Respir J 2009, 34:1100-1110.
76. Morrell N.W., Yang X., Upton P.D., Jourdan K.B., Morgan N., Sheares K.K., et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 2001, 104(7):790-795.
77. Jeffery T.K., Upton P.D., Trembath R.C., Morrell N.W. BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. Am J Physiol Lung Cell Mol Physiol 2005, 288(2):L370-L378.
78. Upton P.D., Morrell N.W. TGF-beta and BMPR-II pharmacology-implications for pulmonary vascular diseases. Curr Opin Pharmacol 2009, 9(3):274-280.
79. Lagna G., Ku M.M., Nguyen P.H., Neuman N.A., Davis B.N., Hata A. Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors. J Biol Chem 2007, 282(51):37244-37255.
80. Abman S.H. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med 2009, 60:13-23.
81. Cacoub P., Dorent R., Maistre G., Nataf P., Carayon A., Piette C., et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol 1993, 71(5):448-450.
82. Giaid A., Yanagisawa M., Langleben D., Michel R.P., Levy R., Shennib H., et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993, 328(24):1732-1739.
83. A receptor and independently of transforming growth factor-beta, increases the connective tissue growth factor in vascular smooth muscle cells. Circ Res 2005, 97(2):125-134.
84. Gurtner H.P., Gertsch M., Salzmann C., Scherrer M., Stucki P., Wyss F. [Are the primary vascular forms of chronic pulmonary heart disease becoming more common?]. Schweiz Med Wochenschr 1968, 98(41):1579-1589.
85. Abenhaim L., Moride Y., Brenot F., Rich S., Benichou J., Kurz X., et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996, 335(9):609-616.
86. Dempsie Y., Morecroft I., Welsh D.J., MacRitchie N.A., Herold N., Loughlin L., et al. Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 2008, 117(22):2928-2937.
87. Weir E.K., Reeve H.L., Huang J.M., Michelakis E., Nelson D.P., Hampl V., et al. Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 1996, 94(9):2216-2220.
88. 2+, independent of membrane potential. Am J Physiol 1999, 277(3 Pt 1):L662-L666.
89. Herve P., Launay J.M., Scrobohaci M.L., Brenot F., Simonneau G., Petitpretz P., et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995, 99(3):249-254.
90. Eddahibi S., Guignabert C., Barlier-Mur A.M., Dewachter L., Fadel E., Dartevelle P., et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 2006, 113(15):1857-1864.
91. Eddahibi S., Humbert M., Fadel E., Raffestin B., Darmon M., Capron F., et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001, 108(8):1141-1150.
92. Long L., MacLean M.R., Jeffery T.K., Morecroft I., Yang X., Rudarakanchana N., et al. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 2006, 98(6):818-827.
93. Yang X., Long L., Southwood M., Rudarakanchana N., Upton P.D., Jeffery T.K., et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005, 96(10):1053-1063.
94. Hassoun P.M., Mouthon L., Barbera J.A., Eddahibi S., Flores S.C., Grimminger F., et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009, 54(Suppl. 1):S10-S19.
95. Tuder R.M., Groves B., Badesch D.B., Voelkel N.F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994, 144(2):275-285.
96. Fartoukh M., Emilie D., Le G.C., Monti G., Simonneau G., Humbert M. Chemokine macrophage inflammatory protein-1alpha mRNA expression in lung biopsy specimens of primary pulmonary hypertension. Chest 1998, 114(Suppl. 1):S50-S51.
97. Humbert M., Monti G., Brenot F., Sitbon O., Portier A., Grangeot-Keros L., et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995, 151(5):1628-1631.
98. Sakamaki F., Kyotani S., Nagaya N., Sato N., Oya H., Satoh T., et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation 2000, 102(22):2720-2725.
99. Dorfmuller P., Perros F., Balabanian K., Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003, 22(2):358-363.
100. Hagen M., Fagan K., Steudel W., Carr M., Lane K., Rodman D.M., et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 2007, 292(6):L1473-L1479.
101. Do e Z., Fukumoto Y., Takaki A., Tawara S., Ohashi J., Nakano M., et al. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J 2009, 73(9):1731-1739.
102. Li F., Xia W., Li A., Zhao C., Sun R. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol Res 2007, 55(1):64-71.
103. Shibata R., Kai H., Seki Y., Kato S., Morimatsu M., Kaibuchi K., et al. Role of Rho-associated kinase in neointima formation after vascular injury. Circulation 2001, 103(2):284-289.
104. Noma K., Rikitake Y., Oyama N., Yan G., Alcaide P., Liu P.Y., et al. ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest 2008, 118(5):1632-1644.
105. Ming X.F., Viswambharan H., Barandier C., Ruffieux J., Kaibuchi K., Rusconi S., et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol 2002, 22(24):8467-8477.
106. Hernandez-Perera O., Perez-Sala D., Soria E., Lamas S. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res 2000, 87(7):616-622.
107. Gorovoy M., Neamu R., Niu J., Vogel S., Predescu D., Miyoshi J., et al. RhoGDI-1 modulation of the activity of monomeric RhoGTPase RhoA regulates endothelial barrier function in mouse lungs. Circ Res 2007, 101(1):50-58.
108. Ridley A.J., Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 1992, 70(3):389-399.
109. Miyata K., Shimokawa H., Kandabashi T., Higo T., Morishige K., Eto Y., et al. Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo. Arterioscler Thromb Vasc Biol 2000, 20(11):2351-2358.
110. van Nieuw Amerongen G.P., van D.S., Vermeer M.A., Collard J.G., van Hinsbergh V.W. Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases. Circ Res 2000, 87(4):335-340.
111. Kishi H., Bao J., Kohama K. Inhibitory effects of ML-9, wortmannin, and Y-27632 on the chemotaxis of vascular smooth muscle cells in response to platelet-derived growth factor-BB. J Biochem 2000, 128(5):719-722.
112. de JP V., Alastalo T.P., Wu J.C., Axelrod J.D., Cooke J.P., Amieva M., et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J Cell Biol 2009, 184(1):83-99.
113. Liu Y., Ren W., Warburton R., Toksoz D., Fanburg B.L. Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells. FASEB J 2009, 23(7):2299-2306.
114. Reynisdottir I., Polyak K., Iavarone A., Massague J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 1995, 9(15):1831-1845.
115. Kawamura C., Kizaki M., Ikeda Y. Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells. Leuk Lymphoma 2002, 43(3):635-639.
116. Liu Y., Suzuki Y.J., Day R.M., Fanburg B.L. Rho kinase-induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin. Circ Res 2004, 95(6):579-586.
117. Walther D.J., Peter J.U., Winter S., Holtje M., Paulmann N., Grohmann M., et al. Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell 2003, 115(7):851-862.
118. Guilluy C., Rolli-Derkinderen M., Tharaux P.L., Melino G., Pacaud P., Loirand G. Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 2007, 282(5):2918-2928.
119. Hill-Eubanks D.C., Gomez M.F., Stevenson A.S., Nelson M.T. NFAT regulation in smooth muscle. Trends Cardiovasc Med 2003, 13(2):56-62.
120. Bonnet S., Rochefort G., Sutendra G., Archer S.L., Haromy A., Webster L., et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A 2007, 104(27):11418-11423.
121. Gonzalez Bosc L.V., Layne J.J., Nelson M.T., Hill-Eubanks D.C. Nuclear factor of activated T cells and serum response factor cooperatively regulate the activity of an alpha-actin intronic enhancer. J Biol Chem 2005, 280(28):26113-26120.
122. de Frutos S., Spangler R., Alo D., Bosc L.V. NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation. J Biol Chem 2007, 282(20):15081-15089.
123. Yaghi A., Sims S.M. Constrictor-induced translocation of NFAT3 in human and rat pulmonary artery smooth muscle. Am J Physiol Lung Cell Mol Physiol 2005, 289(6):L1061-L1074.
124. de Frutos S., Caldwell E., Nitta C.H., Kanagy N.L., Wang J., Wang W., et al. NFATc3 contributes to intermittent hypoxia-induced arterial remodeling in mice. Am J Physiol Heart Circ Physiol 2010, 10.1152/ajpheart.00341.2010.
125. Zhang Y.G., Li J., Li Y.G., Wei R.H. Urotensin II induces phenotypic differentiation, migration, and collagen synthesis of adventitial fibroblasts from rat aorta. J Hypertens 2008, 26(6):1119-1126.
126. Fukumoto Y., Matoba T., Ito A., Tanaka H., Kishi T., Hayashidani S., et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005, 91(3):391-392.
127. Ishikura K., Yamada N., Ito M., Ota S., Nakamura M., Isaka N., et al. Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J 2006, 70(2):174-178.
128. Li F., Xia W., Yuan S., Sun R. Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease. Pediatr Cardiol 2009, 30(3):363-366.
129. Shimoda L.A., Sham J.S., Sylvester J.T. Altered pulmonary vasoreactivity in the chronically hypoxic lung. Physiol Res 2000, 49(5):549-560.
130. Adnot S., Raffestin B., Eddahibi S., Braquet P., Chabrier P.E. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest 1991, 87(1):155-162.
131. MacLean M.R., Sweeney G., Baird M., McCulloch K.M., Houslay M., Morecroft I. 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats. Br J Pharmacol 1996, 119(5):917-930.
132. MacLean M.R., Johnston E.D., McCulloch K.M., Pooley L., Houslay M.D., Sweeney G. Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension. J Pharmacol Exp Ther 1997, 283(2):619-624.
133. Resta T.C., Walker B.R. Chronic hypoxia selectively augments endothelium-dependent pulmonary arterial vasodilation. Am J Physiol 1996, 270(3 Pt 2):H888-H896.
134. Le Cras T.D., Xue C., Rengasamy A., Johns R.A. Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung. Am J Physiol 1996, 270(1 Pt 1):L164-L170.
135. Zhao L., Sebkhi A., Ali O., Wojciak-Stothard B., Mamanova L., Yang Q., et al. Simvastatin and sildenafil combine to attenuate pulmonary hypertension. Eur Respir J 2009, 34(4):948-957.
136. Tyler R.C., Muramatsu M., Abman S.H., Stelzner T.J., Rodman D.M., Bloch K.D., et al. Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension. Am J Physiol 1999, 276(2 Pt 1):L297-L303.
137. Dinh-Xuan A.T., Higenbottam T.W., Clelland C.A., Pepke-Zaba J., Cremona G., Butt A.Y., et al. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 1991, 324(22):1539-1547.
138. Cargill R.I., Lipworth B.J. The role of the renin-angiotensin and natriuretic peptide systems in the pulmonary vasculature. Br J Clin Pharmacol 1995, 40(1):11-18.
139. Ferri C., Bellini C., De A.C., De S.L., Perrone A., Properzi G., et al. Circulating endothelin-1 concentrations in patients with chronic hypoxia. J Clin Pathol 1995, 48(6):519-524.
140. Hironaka E., Hongo M., Sakai A., Mawatari E., Terasawa F., Okumura N., et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003, 60(3):692-699.
141. Guignabert C., Raffestin B., Benferhat R., Raoul W., Zadigue P., Rideau D., et al. Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 2005, 111(21):2812-2819.
142. Shimoda L.A., Sham J.S., Liu Q., Sylvester J.T. Acute and chronic hypoxic pulmonary vasoconstriction: a central role for endothelin-1?. Respir Physiol Neurobiol 2002, 132(1):93-106.
143. Li H., Chen S.J., Chen Y.F., Meng Q.C., Durand J., Oparil S., et al. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 1994, 77(3):1451-1459.
144. Hu J., Discher D.J., Bishopric N.H., Webster K.A. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun 1998, 245(3):894-899.
145. Bonvallet S.T., Zamora M.R., Hasunuma K., Sato K., Hanasato N., Anderson D., et al. BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 1994, 266(4 Pt 2):H1327-H1331.
146. Miyauchi T., Yorikane R., Sakai S., Sakurai T., Okada M., Nishikibe M., et al. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ Res 1993, 73(5):887-897.
147. +currents by endothelin-1 in human pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2001, 281(5):L1115-L1122.
148. Weigand L., Sylvester J.T., Shimoda L.A. Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2006, 290(2):L284-L290.
149. 2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 2008, 295(3):L515-L529.
150. 2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signaling. Am J Physiol Lung Cell Mol Physiol 2004, 287(6):L1220-L1229.
151. Miyata M., Ito M., Sasajima T., Ohira H., Kasukawa R. Effect of a serotonin receptor antagonist on interleukin-6-induced pulmonary hypertension in rats. Chest 2001, 119(2):554-561.
152. Callebert J., Esteve J.M., Herve P., Peoc'h K., Tournois C., Drouet L., et al. Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice. J Pharmacol Exp Ther 2006, 317(2):724-731.
153. Eddahibi S., Hanoun N., Lanfumey L., Lesch K.P., Raffestin B., Hamon M., et al. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000, 105(11):1555-1562.
154. MacLean M.R., Deuchar G.A., Hicks M.N., Morecroft I., Shen S., Sheward J., et al. Overexpression of the 5-hydroxytryptamine transporter gene: effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 2004, 109(17):2150-2155.
155. Homma N., Nagaoka T., Morio Y., Ota H., Gebb S.A., Karoor V., et al. Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation. J Cardiovasc Pharmacol 2007, 50(6):697-702.
156. i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes. Am J Physiol Lung Cell Mol Physiol 2000, 279(5):L884-L894.
157. 2+ channels in pulmonary arterial smooth muscle cells: a novel mechanism of hypoxic pulmonary hypertension. Circ Res 2004, 95(5):496-505.
158. + current in rat pulmonary artery muscle cells. Am J Physiol 1994, 266(1 Pt 2):H365-H370.
159. Osipenko O.N., Alexander D., MacLean M.R., Gurney A.M. Influence of chronic hypoxia on the contributions of non-inactivating and delayed rectifier K currents to the resting potential and tone of rat pulmonary artery smooth muscle. Br J Pharmacol 1998, 124(7):1335-1337.
160. V channel expression and function in pulmonary artery myocytes. Am J Physiol Lung Cell Mol Physiol 2001, 280(4):L801-L812.
161. + channel expression in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 2008, 294(2):L309-L318.
162. 2+ in pulmonary arterial smooth muscle cells. Circ Res 2006, 98(12):1528-1537.
163. Leach R.M., Robertson T.P., Twort C.H., Ward J.P. Hypoxic vasoconstriction in rat pulmonary and mesenteric arteries. Am J Physiol 1994, 266(3 Pt 1):L223-L231.
164. Weissmann N., Dietrich A., Fuchs B., Kalwa H., Ay M., Dumitrascu R., et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A 2006, 103(50):19093-19098.
165. Leach R.M., Treacher D.F. Clinical aspects of hypoxic pulmonary vasoconstriction. Exp Physiol 1995, 80(5):865-875.
166. Robertson T.P., Dipp M., Ward J.P., Aaronson P.I., Evans A.M. 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.
167. Fagan K.A., Oka M., Bauer N.R., Gebb S.A., Ivy D.D., Morris K.G., 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(4):L656-L664.
168. Wang Z., Jin N., Ganguli S., Swartz D.R., Li L., Rhoades R.A. Rho-kinase activation is involved in hypoxia-induced pulmonary vasoconstriction. Am J Respir Cell Mol Biol 2001, 25(5):628-635.
169. 2+-sensitization of rat pulmonary artery. Cardiovasc Res 2008, 77(3):570-579.
170. McMurtry I.F., Petrun M.D., Reeves J.T. Lungs from chronically hypoxic rats have decreased pressor response to acute hypoxia. Am J Physiol 1978, 235(1):H104-H109.
171. Reeve H.L., Michelakis E., Nelson D.P., Weir E.K., Archer S.L. Alterations in a redox oxygen sensing mechanism in chronic hypoxia. J Appl Physiol 2001, 90(6):2249-2256.
172. Wilkinson M., Langhorne C.A., Heath D., Barer G.R., Howard P. A pathophysiological study of 10 cases of hypoxic cor pulmonale. Q J Med 1988, 66(249):65-85.
173. Stenmark K.R., Fagan K.A., Frid M.G. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 2006, 99(7):675-691.
174. Meyrick B., Reid L. Pulmonary hypertension. Anatomic and physiologic correlates. Clin Chest Med 1983, 4(2):199-217.
175. Howell K., Preston R.J., McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation. J Physiol 2003, 547(Pt 1):133-145.
176. Hyvelin J.M., Howell K., Nichol A., Costello C.M., Preston R.J., McLoughlin P. Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res 2005, 97(2):185-191.
177. Stenmark K.R., Gerasimovskaya E., Nemenoff R.A., Das M. Hypoxic activation of adventitial fibroblasts: role in vascular remodeling. Chest 2002, 122(Suppl. 6):S326-S334.
178. Das M., Bouchey D.M., Moore M.J., Hopkins D.C., Nemenoff R.A., Stenmark K.R. Hypoxia-induced proliferative response of vascular adventitial fibroblasts is dependent on g protein-mediated activation of mitogen-activated protein kinases. J Biol Chem 2001, 276(19):15631-15640.
179. Sobin S.S., Tremer H.M., Hardy J.D., Chiodi H.P. Changes in arteriole in acute and chronic hypoxic pulmonary hypertension and recovery in rat. J Appl Physiol 1983, 55(5):1445-1455.
180. Frid M.G., Brunetti J.A., Burke D.L., Carpenter T.C., Davie N.J., Reeves J.T., et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 2006, 168(2):659-669.
181. Aguirre J.I., Morrell N.W., Long L., Clift P., Upton P.D., Polak J.M., et al. Vascular remodeling and ET-1 expression in rat strains with different responses to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 2000, 278(5):L981-L987.
182. 1B/1D-receptor antagonist GR127935. Circ Res 2001, 89(12):1231-1239.
183. Morecroft I., Dempsie Y., Bader M., Walther D.J., Kotnik K., Loughlin L., et al. Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 2007, 49(1):232-236.
184. 1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. Br J Pharmacol 2008, 155(4):606-616.
185. Guilluy C., Sauzeau V., Rolli-Derkinderen M., Guerin P., Sagan C., Pacaud P., et al. Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. Br J Pharmacol 2005, 146(7):1010-1018.
186. Nagaoka T., Gebb S.A., Karoor V., Homma N., Morris K.G., McMurtry I.F., et al. Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 2006, 100(3):996-1002.
187. Oka M., Homma N., Taraseviciene-Stewart L., Morris K.G., Kraskauskas D., Burns N., et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007, 100(6):923-929.
188. Hemnes A.R., Zaiman A., Champion H.C. PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation. Am J Physiol Lung Cell Mol Physiol 2008, 294(1):L24-L33.
189. Broughton B.R., Walker B.R., Resta T.C. Chronic hypoxia induces Rho kinase-dependent myogenic tone in small pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 2008, 294(4):L797-L806.
190. 2+ sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA. Am J Physiol Lung Cell Mol Physiol 2010, 298(2):L232-L242.
191. Knock G.A., Snetkov V.A., Shaifta Y., Drndarski S., Ward J.P., Aaronson P.I. Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery. Cardiovasc Res 2008, 80(3):453-462.
192. 2+ sensitization. Free Radic Biol Med 2009, 46(5):633-642.
193. Liu J.Q., Zelko I.N., Erbynn E.M., Sham J.S., Folz R.J. Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 2006, 290(1):L2-L10.
194. Hoshikawa Y., Ono S., Suzuki S., Tanita T., Chida M., Song C., et al. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol 2001, 90(4):1299-1306.
195. Girgis R.E., Li D., Zhan X., Garcia J.G., Tuder R.M., Hassoun P.M., et al. Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 2003, 285(3):H938-H945.
196. Lee T.M., Chen C.C., Shen H.N., Chang N.C. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (Lond) 2009, 116(6):497-505.
197. Nagaoka T., Morio Y., Casanova N., Bauer N., Gebb S., McMurtry I., et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2004, 287(4):L665-L672.
198. Arias-Stella J., Saldana M. The terminal portion of the pulmonary arterial tree in people native to high altitudes. Circulation 1963, 28:915-925.
199. Groves B.M., Reeves J.T., Sutton J.R., Wagner P.D., Cymerman A., Malconian M.K., et al. Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol 1987, 63(2):521-530.
200. Abe K., Tawara S., Oi K., Hizume T., Uwatoku T., Fukumoto Y., et al. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol 2006, 48(6):280-285.
201. Nagaoka T., Fagan K.A., Gebb S.A., Morris K.G., Suzuki T., Shimokawa H., et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005, 171(5):494-499.
202. McNamara P.J., Murthy P., Kantores C., Teixeira L., Engelberts D., van V.T., 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(2):L205-L213.
203. Jankov R.P., McNamara P.J. Inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn: when is it enough?. J Crit Care 2005, 20(3):294-295.
204. Abe K., Shimokawa H., Morikawa K., Uwatoku T., Oi K., Matsumoto Y., et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004, 94(3):385-393.
205. 899X mice. Am J Respir Crit Care Med 2010, 179:A1798.
206. Ghisdal P., Vandenberg G., Morel N. Rho-dependent kinase is involved in agonist-activated calcium entry in rat arteries. J Physiol 2003, 551(Pt 3):855-867.
207. Takemoto M., Sun J., Hiroki J., Shimokawa H., Liao J.K. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 2002, 106(1):57-62.
208. Owens G.K. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 1995, 75(3):487-517.
209. Funakoshi Y., Ichiki T., Shimokawa H., Egashira K., Takeda K., Kaibuchi K., et al. Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension 2001, 38(1):100-104.
210. Yamamoto Y., Ikegaki I., Sasaki Y., Uchida T. The protein kinase inhibitor fasudil protects against ischemic myocardial injury induced by endothelin-1 in the rabbit. J Cardiovasc Pharmacol 2000, 35(2):203-211.
211. Sauzeau V., Le M.E., Bertoglio J., Scalbert E., Pacaud P., Loirand G. Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res 2001, 88(11):1102-1104.
212. Kanno S., Wu Y.J., Lee P.C., Billiar T.R., Ho C. Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats. Circulation 2001, 104(8):945-950.
213. Channick R., Badesch D.B., Tapson V.F., Simonneau G., Robbins I., Frost A., et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a placebo-controlled study. J Heart Lung Transpl 2001, 20(2):262-263.
214. Qi J., Du J., Tang X., Li J., Wei B., Tang C. The upregulation of endothelial nitric oxide synthase and urotensin-II is associated with pulmonary hypertension and vascular diseases in rats produced by aortocaval shunting. Heart Vessels 2004, 19(2):81-88.
215. Nishimura T., Faul J.L., Berry G.J., Vaszar L.T., Qiu D., Pearl R.G., et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 2002, 166(10):1403-1408.
216. Wojciak-Stothard B. New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling. Postgrad Med J 2008, 84(993):348-353.
217. WAF1/Cip1, is required for inhibition of hypoxia-induced pulmonary hypertension and remodeling by heparin in mice. Circ Res 2005, 97(9):937-945.
218. Nasu K., Tsuno A., Hirao M., Kobayashi H., Yuge A., Narahara H. Heparin is a promising agent for the treatment of endometriosis-associated fibrosis. Fertil Steril 2009, 94(1):46-51.
219. Aznar S., Lacal J.C. Rho signals to cell growth and apoptosis. Cancer Lett 2001, 165(1):1-10.