2015 ATVB plenary lecture: Translational research on rho-kinase in cardiovascular medicine

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 35, Issue 8, 2015, Pages 1756-1769

  Shimokawa, Hiroaki ^a   Satoh, Kimio ^a  

^a TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

cardiovascular disease; heart failure; hypertension; inflammation; rho associated kinases

Indexed keywords

RAS PROTEIN; RHO KINASE; CARDIOVASCULAR AGENT; PROTEIN KINASE INHIBITOR;

ANGINA PECTORIS; AORTA ANEURYSM; APOPTOSIS; ARTERIOSCLEROSIS; ATHEROSCLEROSIS; CARDIOVASCULAR SYSTEM; CELL FUNCTION; CELL INTERACTION; CELL MOTILITY; CELL PROLIFERATION; CORONARY ARTERY SPASM; DISEASE SEVERITY; ENDOTHELIUM CELL; ENZYME ACTIVITY; HEART FAILURE; HEART MUSCLE ISCHEMIA; HEART VENTRICLE HYPERTROPHY; HOMEOSTASIS; HUMAN; MULTIGENE FAMILY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN FUNCTION; PULMONARY HYPERTENSION; REPERFUSION INJURY; REVIEW; TRANSLATIONAL RESEARCH; TREATMENT RESPONSE; VASCULAR SMOOTH MUSCLE CELL; ANIMAL; ANTAGONISTS AND INHIBITORS; CARDIOVASCULAR DISEASES; DISEASE MODEL; DRUG EFFECTS; ENZYMOLOGY; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PATHOPHYSIOLOGY; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE;

ANIMALS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; DISEASE MODELS, ANIMAL; ENDOTHELIUM, VASCULAR; HUMANS; MOLECULAR TARGETED THERAPY; MUSCLE, SMOOTH, VASCULAR; PROTEIN KINASE INHIBITORS; RHO-ASSOCIATED KINASES; SIGNAL TRANSDUCTION; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84938067846     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.115.305353     Document Type: Review

References (180)

1. Shimokawa H., 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. Eur Heart J 2014 35 3180 3193. doi: 10.1093/eurheartj/ehu427
2. Shimokawa H, Takeshita A., Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005 25 1767 1775. doi: 10.1161/01.ATV.0000176193.83629.c8
3. Loirand G, Pacaud P., The role of Rho protein signaling in hypertension. Nat Rev Cardiol 2010 7 637 647. doi: 10.1038/nrcardio.2010.136
4. 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 32 39
5. Takai Y, Sasaki T, Matozaki T., Small GTP-binding proteins. Physiol Rev 2001 81 153 208
6. Rikitake Y, Liao JK., ROCKs as therapeutic targets in cardiovascular diseases. Expert Rev Cardiovasc Ther 2005 3 441 451. doi: 10.1586/14779072.3.3.441
7. Etienne-Manneville S, Hall A., Rho GTPases in cell biology. Nature 2002 420 629 635. doi: 10.1038/nature01148
8. Schmidt A, Hall A., Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 2002 16 1587 1609. doi: 10.1101/gad.1003302
9. Bernards A., GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta 2003 1603 47 82
10. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K., Regulation of myosin phosphatase by Rho and Rho-Associated kinase (Rho-kinase). Science 1996 273 245 248
11. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K., Phosphorylation and activation of myosin by Rho-Associated kinase (Rho-kinase). J Biol Chem 1996 271 20246 20249
12. Somlyo AP, Somlyo AV., Signal transduction and regulation in smooth muscle. Nature 1994 372 231 236. doi: 10.1038/372231a0
13. Hirata K, Kikuchi A, Sasaki T, Kuroda S, Kaibuchi K, Matsuura Y, Seki H, Saida K, Takai Y., Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction. J Biol Chem 1992 267 8719 8722
14. Gong MC, Iizuka K, Nixon G, Browne JP, Hall A, Eccleston JF, Sugai M, Kobayashi S, Somlyo AV, Somlyo AP., Role of guanine nucleotide-binding proteins-ras-family or trimeric proteins or both-in Ca2+ sensitization of smooth muscle. Proc Natl Acad Sci U S A 1996 93 1340 1345
15. Wirth A, Benyó Z, Lukasova M, Leutgeb B, Wettschureck N, Gorbey S, Orsy P, Horváth B, Maser-Gluth C, Greiner E, Lemmer B, Schütz G, Gutkind JS, Offermanns S., G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med 2008 14 64 68. doi: 10.1038/nm1666
16. Nishioka T, Shohag MH, Amano M, Kaibuchi K., Developing novel methods to search for substrates of protein kinases such as Rho-kinase. Biochim Biophys Acta 2015. in press. doi: 10.1016/j.bbapap.2015.03.001
17. Vanhoutte PM., Endothelium-derived free radicals: for worse and for better. J Clin Invest 2001 107 23 25. doi: 10.1172/JCI11832
18. Shimokawa H., Primary endothelial dysfunction: atherosclerosis. J Mol Cell Cardiol 1999 31 23 37. doi: 10.1006/jmcc.1998.0841
19. Shimokawa H, Tomoike H, Nabeyama S, Yamamoto H, Araki H, Nakamura M, Ishii Y, Tanaka K., Coronary artery spasm induced in atherosclerotic miniature swine. Science 1983 221 560 562
20. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A., Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 2000 106 1521 1530. doi: 10.1172/JCI10506
21. Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder MA, Hatanaka M, Fujiki T, Maeda H, Takahashi S, Takeshita A., Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest 2003 112 1871 1879. doi: 10.1172/JCI19351
22. Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kunihiro I, Mukai Y, Hirakawa Y, Takeshita A., Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. Biochem Biophys Res Commun 2002 290 909 913. doi: 10.1006/bbrc.2001.6278
23. Takaki A, Morikawa K, Tsutsui M, Murayama Y, Tekes E, Yamagishi H, Ohashi J, Yada T, Yanagihara N, Shimokawa H., Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 2008 205 2053 2063. doi: 10.1084/jem.20080106
24. Shimokawa H., Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pflugers Arch 2010 459 915 922. doi: 10.1007/s00424-010-0790-8
25. Shimokawa H., Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Pharmacol 2002 39 319 327
26. Ichikawa K, Ito M, Hartshorne DJ., Phosphorylation of the large subunit of myosin phosphatase and inhibition of phosphatase activity. J Biol Chem 1996 271 4733 4740
27. Loirand G, Guérin P, Pacaud P., Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006 98 322 334. doi: 10.1161/01.RES.0000201960.04223.3c
28. Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K., Rho-Associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 1996 15 2208 2216
29. Riento K, Ridley AJ., ROCKs: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 2003 4 446 456. doi: 10.1038/nrm1128
30. Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H., Mechanism of action of a novel antivasospasm drug, HA1077. J Pharmacol Exp Ther 1987 241 1033 1040
31. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S., Calcium sensitization of smooth muscle mediated by a Rho-Associated protein kinase in hypertension. Nature 1997 389 990 994. doi: 10.1038/40187
32. Davies SP, Reddy H, Caivano M, Cohen P., Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000 351 pt 1 95 105
33. Shimokawa H, Seto M, Katsumata N, Amano M, Kozai T, Yamawaki T, Kuwata K, Kandabashi T, Egashira K, Ikegaki I, Asano T, Kaibuchi K, Takeshita A., Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999 43 1029 1039
34. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A., Long-Term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res 2003 93 767 775. doi: 10.1161/01.RES.0000096650.91688.28
35. Huveneers S, Daemen MJ, Hordijk PL., Between Rho(k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res 2015 116 895 908. doi: 10.1161/CIRCRESAHA.116.305720
36. Chapados R, Abe K, Ihida-Stansbury K, McKean D, Gates AT, Kern M, Merklinger S, Elliott J, Plant A, Shimokawa H, Jones PL., ROCK controls matrix synthesis in vascular smooth muscle cells: coupling vasoconstriction to vascular remodeling. Circ Res 2006 99 837 844. doi: 10.1161/01.RES.0000246172.77441.f1
37. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV., Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 2012 485 512 516. doi: 10.1038/nature11087
38. Zhou Q, Liao JK., Rho kinase: an important mediator of atherosclerosis and vascular disease. Curr Pharm Des 2009 15 3108 3115
39. Yao L, Chandra S, Toque HA, Bhatta A, Rojas M, Caldwell RB, Caldwell RW., Prevention of diabetes-induced arginase activation and vascular dysfunction by Rho kinase (ROCK) knockout. Cardiovasc Res 2013 97 509 519. doi: 10.1093/cvr/cvs371
40. Noda K, Godo S, Saito H, Tsutsui M, Shimokawa H., Opposing roles of nitric oxide and rho-kinase in lipid metabolism in mice. Tohoku J Exp Med 2015 235 171 183. doi: 10.1620/tjem.235.171
41. Takemoto M, Liao JK., Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001 21 1712 1719
42. Suzuki J, Jin ZG, Meoli DF, Matoba T, Berk BC., Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells. Circ Res 2006 98 811 817. doi: 10.1161/01.RES.0000216405.85080.a6
43. Satoh K, Matoba T, Suzuki J, O'Dell MR, Nigro P, Cui Z, Mohan A, Pan S, Li L, Jin ZG, Yan C, Abe J, Berk BC., Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation. Circulation 2008 117 3088 3098. doi: 10.1161/CIRCULATIONAHA.107.756106
44. Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, Takai Y, Williams CL, Liao JK, Shimokawa H., Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 2013 33 1591 1600. doi: 10.1161/ATVBAHA.112.300922
45. Streb H, Irvine RF, Berridge MJ, Schulz I., Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-Trisphosphate. Nature 1983 306 67 69
46. Berridge MJ., Smooth muscle cell calcium activation mechanisms. J Physiol 2008 586 pt 21 5047 5061. doi: 10.1113/jphysiol.2008.160440
47. Ikebe M, Hartshorne DJ., Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase. J Biol Chem 1985 260 10027 10031
48. Seto M, Sasaki Y, Sasaki Y., Stimulus-specific patterns of myosin light chain phosphorylation in smooth muscle of rabbit thoracic artery. Pflugers Arch 1990 415 484 489
49. Cai Y, Nagel DJ, Zhou Q, Cygnar KD, Zhao H, Li F, Pi X, Knight PA, Yan C., Role of cAMP-phosphodiesterase 1C signaling in regulating growth factor receptor stability, vascular smooth muscle cell growth, migration, and neointimal hyperplasia. Circ Res 2015 116 1120 1132. doi: 10.1161/CIRCRESAHA.116.304408
50. Satoh K, Kikuchi N, Kurosawa R, Shimokawa H., PDE1C negatively regulates growth factor receptor degradation and promotes VSMC proliferation. Circ Res 2015 116 1098 1100. doi: 10.1161/CIRCRESAHA.115.306139
51. Seto M, Yano K, Sasaki Y, Azuma H., Intimal hyperplasia enhances myosin phosphorylation in rabbit carotid artery. Exp Mol Pathol 1993 58 1 13. doi: 10.1006/exmp.1993.1001
52. Kitazawa T, Masuo M, Somlyo AP., G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc Natl Acad Sci U S A 1991 88 9307 9310
53. Alessi D, MacDougall LK, Sola MM, 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 1023 1035
54. Shimizu H, Ito M, Miyahara M, Ichikawa K, Okubo S, Konishi T, Naka M, Tanaka T, Hirano K, Hartshorne DJ., Characterization of the myosin-binding subunit of smooth muscle myosin phosphatase. J Biol Chem 1994 269 30407 30411
55. Chihara K, Amano M, Nakamura N, Yano T, Shibata M, Tokui T, Ichikawa H, Ikebe R, Ikebe M, Kaibuchi K., Cytoskeletal rearrangements and transcriptional activation of c-fos serum response element by Rho-kinase. J Biol Chem 1997 272 25121 25127
56. Kureishi Y, Kobayashi S, Amano M, Kimura K, Kanaide H, Nakano T, Kaibuchi K, Ito M., Rho-Associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem 1997 272 12257 12260
57. Amano M, Chihara K, Nakamura N, Fukata Y, Yano T, Shibata M, Ikebe M, Kaibuchi K., Myosin II activation promotes neurite retraction during the action of Rho and Rho-kinase. Genes Cells 1998 3 177 188
58. Berk BC, Alexander RW, Brock TA, Gimbrone MA Jr, Webb RC., Vasoconstriction: a new activity for platelet-derived growth factor. Science 1986 232 87 90
59. Griendling KK, Berk BC, Ganz P, Gimbrone MA Jr, Alexander RW., Angiotensin II stimulation of vascular smooth muscle phosphoinositide metabolism. State of the art lecture. Hypertension 1987 9 6 pt 2 III181 III185
60. Berk BC., Vascular smooth muscle growth: autocrine growth mechanisms. Physiol Rev 2001 81 999 1030
61. Taniyama Y, Griendling KK., Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension 2003 42 1075 1081. doi: 10.1161/01.HYP.0000100443.09293.4F
62. Satoh K, Godo S, Saito H, Enkhjargal B, Shimokawa H., Dual roles of vascular-derived reactive oxygen species-with a special reference to hydrogen peroxide and cyclophilin A. J Mol Cell Cardiol 2014 73 50 56. doi: 10.1016/j.yjmcc.2013.12.022
63. Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth JD, Berk BC., Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res 2000 87 789 796
64. Satoh K, Shimokawa H, Berk BC., Cyclophilin A: promising new target in cardiovascular therapy. Circ J 2010 74 2249 2256
65. Satoh K, Nigro P, Berk BC., Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A. Antioxid Redox Signal 2010 12 675 682. doi: 10.1089/ars.2009.2875
66. Mackay DJ, Hall A., Rho GTPases. J Biol Chem 1998 273 20685 20688
67. Neco P, Giner D, Viniegra S, Borges R, Villarroel A, Gutiérrez LM., New roles of myosin II during vesicle transport and fusion in chromaffin cells. J Biol Chem 2004 279 27450 27457. doi: 10.1074/jbc.M311462200
68. Satoh K, Nigro P, Matoba T, O'Dell MR, Cui Z, Shi X, Mohan A, Yan C, Abe J, Illig KA, Berk BC., Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med 2009 15 649 656. doi: 10.1038/nm.1958
69. Jin ZG, Lungu AO, Xie L, Wang M, Wong C, Berk BC., Cyclophilin A is a proinflammatory cytokine that activates endothelial cells. Arterioscler Thromb Vasc Biol 2004 24 1186 1191. doi: 10.1161/01.ATV.0000130664.51010.28
70. Kim H, Kim WJ, Jeon ST, Koh EM, Cha HS, Ahn KS, Lee WH., Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages. Clin Immunol 2005 116 217 224. doi: 10.1016/j.clim.2005.05.004
71. Damsker JM, Bukrinsky MI, Constant SL., Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A. J Leukoc Biol 2007 82 613 618. doi: 10.1189/jlb.0506317
72. Yang Y, Lu N, Zhou J, Chen ZN, Zhu P., Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis. Rheumatology (Oxford) 2008 47 1299 1310. doi: 10.1093/rheumatology/ken225
73. Wang L, Wang CH, Jia JF, Ma XK, Li Y, Zhu HB, Tang H, Chen ZN, Zhu P., Contribution of cyclophilin A to the regulation of inflammatory processes in rheumatoid arthritis. J Clin Immunol 2010 30 24 33. doi: 10.1007/s10875-009-9329-1
74. Elvers M, Herrmann A, Seizer P, Münzer P, Beck S, Schönberger T, Borst O, Martin-Romero FJ, Lang F, May AE, Gawaz M., Intracellular cyclophilin A is an important Ca(2+) regulator in platelets and critically involved in arterial thrombus formation. Blood 2012 120 1317 1326. doi: 10.1182/blood-2011-12-398438
75. Seizer P, Ungern-Sternberg SN, Schönberger T, Borst O, Münzer P, Schmidt EM, Mack AF, Heinzmann D, Chatterjee M, Langer H, Malešević M, Lang F, Gawaz M, Fischer G, May AE., Extracellular cyclophilin A activates platelets via EMMPRIN (CD147) and PI3K/Akt signaling, which promotes platelet adhesion and thrombus formation in vitro and in vivo. Arterioscler Thromb Vasc Biol 2015 35 655 663. doi: 10.1161/ATVBAHA.114.305112
76. Seizer P, Gawaz M, May AE., Cyclophilin A and EMMPRIN (CD147) in cardiovascular diseases. Cardiovasc Res 2014 102 17 23. doi: 10.1093/cvr/cvu035
77. Eto M, Barandiér C, Rathgeb L, Kozai T, Joch H, Yang Z, Lüscher TF., Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: role of Rho/ROCK and mitogen-Activated protein kinase. Circ Res 2001 89 583 590
78. Alexander RW., Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. Hypertension 1995 25 155 161
79. Omar HA, Cherry PD, Mortelliti MP, Burke-Wolin T, Wolin MS., Inhibition of coronary artery superoxide dismutase attenuates endothelium-dependent and-independent nitrovasodilator relaxation. Circ Res 1991 69 601 608
80. Baas AS, Berk BC., Differential activation of mitogen-Activated protein kinases by H2O2 and O2-in vascular smooth muscle cells. Circ Res 1995 77 29 36
81. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW., Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994 74 1141 1148
82. Funakoshi Y, Ichiki T, Shimokawa H, Egashira K, Takeda K, Kaibuchi K, Takeya M, Yoshimura T, Takeshita A., Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension 2001 38 100 104
83. Takeda K, Ichiki T, Tokunou T, Iino N, Fujii S, Kitabatake A, Shimokawa H, Takeshita A., Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. Arterioscler Thromb Vasc Biol 2001 21 868 873
84. Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G., The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med 2010 16 183 190. doi: 10.1038/nm.2079
85. van Nieuw Amerongen GP, van Delft S, Vermeer MA, Collard JG, van Hinsbergh VW., Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases. Circ Res 2000 87 335 340
86. Seasholtz TM, Majumdar M, Kaplan DD, Brown JH., Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration. Circ Res 1999 84 1186 1193
87. 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 128 719 722
88. Himpens B, Kitazawa T, Somlyo AP., Agonist-dependent modulation of Ca2+ sensitivity in rabbit pulmonary artery smooth muscle. Pflugers Arch 1990 417 21 28
89. Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Vaillant N, Gadeau AP, Desgranges C, Scalbert E, Chardin P, Pacaud P, Loirand G., P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors are coupled to Rho and Rho kinase activation in vascular myocytes. Am J Physiol Heart Circ Physiol 2000 278 H1751 H1761
90. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK., Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 2002 106 57 62
91. Radeff JM, Nagy Z, Stern PH., Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promoter activity in osteoblastic cells. J Bone Miner Res 2004 19 1882 1891. doi: 10.1359/JBMR.040806
92. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, Kaibuchi K, Takeshita A., Long-Term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation 2004 109 2234 2239. doi: 10.1161/01.CIR.0000127939.16111.58
93. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Kaibuchi K, Takeshita A., Long-Term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res 2004 94 46 52. doi: 10.1161/01.RES.0000107196.21335.2B
94. Wang F, Okamoto Y, Inoki I, Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice. J Clin Invest 2010 120 3979 3995. doi: 10.1172/JCI42315
95. Hiroki J, Shimokawa H, Higashi M, Morikawa K, Kandabashi T, Kawamura N, Kubota T, Ichiki T, Amano M, Kaibuchi K, Takeshita A., Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004 37 537 546. doi: 10.1016/j.yjmcc.2004.05.008
96. Oi K, Shimokawa H, Hiroki J, Uwatoku T, Abe K, Matsumoto Y, Nakajima Y, Nakajima K, Takeichi S, Takeshita A., Remnant lipoproteins from patients with sudden cardiac death enhance coronary vasospastic activity through upregulation of Rho-kinase. Arterioscler Thromb Vasc Biol 2004 24 918 922. doi: 10.1161/01.ATV.0000126678.93747.80
97. Shimokawa H, Rashid M., Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci 2007 28 296 302. doi: 10.1016/j.tips.2007.04.006
98. Satoh K, Fukumoto Y, Shimokawa H., Rho-kinase: important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol 2011 301 H287 H296. doi: 10.1152/ajpheart.00327.2011
99. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, Nakashima M, Kato K., Anti-Anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol 2002 40 751 761
100. Eto Y, Shimokawa H, Hiroki J, Morishige K, Kandabashi T, Matsumoto Y, Amano M, Hoshijima M, Kaibuchi K, Takeshita A., Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs. Am J Physiol Heart Circ Physiol 2000 278 H1744 H1750
101. Sawada N, Itoh H, Ueyama K, Yamashita J, Doi K, Chun TH, Inoue M, Masatsugu K, Saito T, Fukunaga Y, Sakaguchi S, Arai H, Ohno N, Komeda M, Nakao K., Inhibition of rho-Associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation 2000 101 2030 2033
102. Shibata R, Kai H, Seki Y, Kato S, Morimatsu M, Kaibuchi K, Imaizumi T., Role of Rho-Associated kinase in neointima formation after vascular injury. Circulation 2001 103 284 289
103. Miyata K, Shimokawa H, Kandabashi T, Higo T, Morishige K, Eto Y, Egashira K, Kaibuchi K, Takeshita A., Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo. Arterioscler Thromb Vasc Biol 2000 20 2351 2358
104. Shimokawa H, Ito A, Fukumoto Y, Kadokami T, Nakaike R, Sakata M, Takayanagi T, Egashira K, Takeshita A., Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J Clin Invest 1996 97 769 776. doi: 10.1172/JCI118476
105. Shimokawa H, Morishige K, Miyata K, Kandabashi T, Eto Y, Ikegaki I, Asano T, Kaibuchi K, Takeshita A., Long-Term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo. Cardiovasc Res 2001 51 169 177
106. Matsumoto Y, Uwatoku T, Oi K, Abe K, Hattori T, Morishige K, Eto Y, Fukumoto Y, Nakamura K, Shibata Y, Matsuda T, Takeshita A, Shimokawa H., Long-Term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: involvement of multiple mechanisms. Arterioscler Thromb Vasc Biol 2004 24 181 186. doi: 10.1161/01.ATV.0000105053.46994.5B
107. Takagi Y, Yasuda S, Takahashi J, Takeda M, Nakayama M, Ito K, Hirose M, Wakayama Y, Fukuda K, Shimokawa H., Importance of dual induction tests for coronary vasospasm and ventricular fibrillation in patients surviving out-of-hospital cardiac arrest. Circ J 2009 73 767 769
108. Hizume T, Morikawa K, Takaki A, Abe K, Sunagawa K, Amano M, Kaibuchi K, Kubo C, Shimokawa H., Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm. Circ Res 2006 99 767 775. doi: 10.1161/01.RES.0000244093.69985.2f
109. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, Higo T, Egashira K, Takahashi S, Kaibuchi K, Takeshita A., Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation 2000 101 1319 1323
110. Katsumata N, Shimokawa H, Seto M, Kozai T, Yamawaki T, Kuwata K, Egashira K, Ikegaki I, Asano T, Sasaki Y, Takeshita A., Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta. Circulation 1997 96 4357 4363
111. Shimokawa H., Cellular and molecular mechanisms of coronary artery spasm: lessons from animal models. Jpn Circ J 2000 64 1-12
112. Ito A, Shimokawa H, Kadokami T, Fukumoto Y, Owada MK, Shiraishi T, Nakaike R, Takayanagi T, Egashira K, Takeshita A., Tyrosine kinase inhibitor suppresses coronary arteriosclerotic changes and vasospastic responses induced by chronic treatment with interleukin-1 beta in pigs in vivo. J Clin Invest 1995 96 1288 1294. doi: 10.1172/JCI118163
113. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Eto Y, Morishige K, Matsumoto Y, Obara K, Nakayama K, Takahashi S, Takeshita A., Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol 2003 23 2209 2214. doi: 10.1161/01.ATV.0000104010.87348.26
114. Yamakawa T, Tanaka S, Numaguchi K, Yamakawa Y, Motley ED, Ichihara S, Inagami T., Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. Hypertension 2000 35 1 pt 2 313 318
115. Kandabashi T, Shimokawa H, Mukai Y, Matoba T, Kunihiro I, Morikawa K, Ito M, Takahashi S, Kaibuchi K, Takeshita A., Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries. Arterioscler Thromb Vasc Biol 2002 22 243 248
116. Libby P., Inflammation in atherosclerosis. Nature 2002 420 868 874. doi: 10.1038/nature01323
117. Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, Nagai T, Kaneko S, Komuro I., Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation 2006 114 953 960. doi: 10.1161/CIRCULATIONAHA.106.626606
118. Griendling KK, FitzGerald GA., Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation 2003 108 2034 2040. doi: 10.1161/01.CIR.0000093661.90582.c4
119. Bruemmer D, Collins AR, Noh G, Wang W, Territo M, Arias-Magallona S, Fishbein MC, Blaschke F, Kintscher U, Graf K, Law RE, Hsueh WA., Angiotensin II-Accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. J Clin Invest 2003 112 1318 1331. doi: 10.1172/JCI18141
120. Yoshimura K, Aoki H, Ikeda Y, Fujii K, Akiyama N, Furutani A, Hoshii Y, Tanaka N, Ricci R, Ishihara T, Esato K, Hamano K, Matsuzaki M., Regression of abdominal aortic aneurysm by inhibition of c-Jun N-Terminal kinase. Nat Med 2005 11 1330 1338. doi: 10.1038/nm1335
121. Sun J, Sukhova GK, Yang M, Wolters PJ, MacFarlane LA, Libby P, Sun C, Zhang Y, Liu J, Ennis TL, Knispel R, Xiong W, Thompson RW, Baxter BT, Shi GP., Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 2007 117 3359 3368. doi: 10.1172/JCI31311
122. Daugherty A, Manning MW, Cassis LA., Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. J Clin Invest 2000 105 1605 1612. doi: 10.1172/JCI7818
123. Daugherty A, Cassis L., Angiotensin II-mediated development of vascular diseases. Trends Cardiovasc Med 2004 14 117 120. doi: 10.1016/j.tcm.2004.01.002
124. Thomas M, Gavrila D, McCormick ML, Miller FJ Jr, Daugherty A, Cassis LA, Dellsperger KC, Weintraub NL., Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation 2006 114 404 413. doi: 10.1161/CIRCULATIONAHA.105.607168
125. Gavazzi G, Deffert C, Trocme C, Schäppi M, Herrmann FR, Krause KH., NOX1 deficiency protects from aortic dissection in response to angiotensin II. Hypertension 2007 50 189 196. doi: 10.1161/HYPERTENSIONAHA.107.089706
126. Thompson RW, Baxter BT., MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial. Ann N Y Acad Sci 1999 878 159 178
127. Manning MW, Cassis LA, Daugherty A., Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2003 23 483 488. doi: 10.1161/01.ATV.0000058404.92759.32
128. Wang YX, Martin-McNulty B, da Cunha V, Fasudil, a Rho-kinase inhibitor, attenuates angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice by inhibiting apoptosis and proteolysis. Circulation 2005 111 2219 2226. doi: 10.1161/01.CIR.0000163544.17221.BE
129. Liao DF, Jin ZG, Baas AS, Daum G, Gygi SP, Aebersold R, Berk BC., Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J Biol Chem 2000 275 189 196
130. Khromykh LM, Kulikova NL, Anfalova TV, Muranova TA, Abramov VM, Vasiliev AM, Khlebnikov VS, Kazansky DB., Cyclophilin A produced by thymocytes regulates the migration of murine bone marrow cells. Cell Immunol 2007 249 46 53. doi: 10.1016/j.cellimm.2007.11.002
131. Weintraub NL., Understanding abdominal aortic aneurysm. N Engl J Med 2009 361 1114 1116. doi: 10.1056/NEJMcibr0905244
132. Yada T, Shimokawa H, Hiramatsu O, Kajita T, Shigeto F, Tanaka E, Shinozaki Y, Mori H, Kiyooka T, Katsura M, Ohkuma S, Goto M, Ogasawara Y, Kajiya F., Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo. J Am Coll Cardiol 2005 45 599 607. doi: 10.1016/j.jacc.2004.10.053
133. Sato S, Ikegaki I, Asano T, Shimokawa H., Antiischemic properties of fasudil in experimental models of vasospastic angina. Jpn J Pharmacol 2001 87 34 40
134. Utsunomiya T, Satoh S, Ikegaki I, Toshima Y, Asano T, Shimokawa H., Antianginal effects of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina. Br J Pharmacol 2001 134 1724 1730. doi: 10.1038/sj.bjp.0704410
135. Satoh Si, Ikegaki I, Toshima Y, Watanabe A, Asano T, Shimokawa H., Effects of Rho-kinase inhibitor on vasopressin-induced chronic myocardial damage in rats. Life Sci 2002 72 103 112
136. Ikeda S, Satoh K, Kikuchi N, Miyata S, Suzuki K, Omura J, Shimizu T, Kobayashi K, Kobayashi K, Fukumoto Y, Sakata Y, Shimokawa H., Crucial role of rho-kinase in pressure overload-induced right ventricular hypertrophy and dysfunction in mice. Arterioscler Thromb Vasc Biol 2014 34 1260 1271. doi: 10.1161/ATVBAHA.114.303320
137. Takefuji M, Krüger M, Sivaraj KK, Kaibuchi K, Offermanns S, Wettschureck N., RhoGEF12 controls cardiac remodeling by integrating G protein-And integrin-dependent signaling cascades. J Exp Med 2013 210 665 673. doi: 10.1084/jem.20122126
138. Brakebusch C, Fässler R., The integrin-Actin connection, an eternal love affair. EMBO J 2003 22 2324 2333. doi: 10.1093/emboj/cdg245
139. Zhao XH, Laschinger C, Arora P, Szászi K, Kapus A, McCulloch CA., Force activates smooth muscle alpha-Actin promoter activity through the Rho signaling pathway. J Cell Sci 2007 120 pt 10 1801 1809. doi: 10.1242/jcs.001586
140. Mehta PK, Griendling KK., Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007 292 C82 C97. doi: 10.1152/ajpcell.00287.2006
141. Sadoshima J, Xu Y, Slayter HS, Izumo S., Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993 75 977 984
142. Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T, Namba M., Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-Alpha and angiotensin II. Circulation 1998 98 794 799
143. Akki A, Zhang M, Murdoch C, Brewer A, Shah AM., NADPH oxidase signaling and cardiac myocyte function. J Mol Cell Cardiol 2009 47 15 22. doi: 10.1016/j.yjmcc.2009.04.004
144. Shibata R, Ouchi N, Murohara T., Adiponectin and cardiovascular disease. Circ J 2009 73 608 614
145. Vahebi S, Kobayashi T, Warren CM, de Tombe PP, Solaro RJ., Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin. Circ Res 2005 96 740 747. doi: 10.1161/01.RES.0000162457.56568.7d
146. Fukui S, Fukumoto Y, Suzuki J, Saji K, Nawata J, Tawara S, Shinozaki T, Kagaya Y, Shimokawa H., Long-Term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats. J Cardiovasc Pharmacol 2008 51 317 326. doi: 10.1097/FJC.0b013e31816533b7
147. Takimoto E, Kass DA., Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 2007 49 241 248. doi: 10.1161/01.HYP.0000254415.31362.a7
148. Satoh K, Nigro P, Zeidan A, Soe NN, Jaffré F, Oikawa M, O'Dell MR, Cui Z, Menon P, Lu Y, Mohan A, Yan C, Blaxall BC, Berk BC., Cyclophilin A promotes cardiac hypertrophy in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2011 31 1116 1123. doi: 10.1161/ATVBAHA.110.214601
149. Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Hiroki J, Kaibuchi K, Takeshita A., Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J 2001 15 1062 1064
150. Ito K, Hirooka Y, Sakai K, Kishi T, Kaibuchi K, Shimokawa H, Takeshita A., Rho/Rho-kinase pathway in brain stem contributes to blood pressure regulation via sympathetic nervous system: possible involvement in neural mechanisms of hypertension. Circ Res 2003 92 1337 1343. doi: 10.1161/01.RES.0000079941.59846.D4
151. Ito K, Hirooka Y, Kishi T, Kimura Y, Kaibuchi K, Shimokawa H, Takeshita A., Rho/Rho-kinase pathway in the brainstem contributes to hypertension caused by chronic nitric oxide synthase inhibition. Hypertension 2004 43 156 162. doi: 10.1161/01.HYP.0000114602.82140.a4
152. Haack KK, Gao L, Schiller AM, Curry PL, Pellegrino PR, Zucker IH., Central Rho kinase inhibition restores baroreflex sensitivity and angiotensin II type 1 receptor protein imbalance in conscious rabbits with chronic heart failure. Hypertension 2013 61 723 729. doi: 10.1161/HYPERTENSIONAHA.111.00396
153. Ito K, Hirooka Y, Kimura Y, Shimokawa H, Takeshita A., Effects of hydroxyfasudil administered to the nucleus tractus solitarii on blood pressure and heart rate in spontaneously hypertensive rats. Clin Exp Hypertens 2005 27 269 277
154. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshit A., Long-Term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004 94 385 393. doi: 10.1161/01.RES.0000111804.34509.94
155. Abe K, Tawara S, Oi K, Hizume T, Uwatoku T, Fukumoto Y, Kaibuchi K, Shimokawa H., Long-Term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol 2006 48 280 285. doi: 10.1097/01.fjc.0000248244.64430.4a
156. Shimizu T, Fukumoto Y, Tanaka S, Satoh K, Ikeda S, Shimokawa H., Crucial role of ROCK2 in vascular smooth muscle cells for hypoxia-induced pulmonary hypertension in mice. Arterioscler Thromb Vasc Biol 2013 33 2780 2791. doi: 10.1161/ATVBAHA.113.301357
157. Satoh K, Satoh T, Kikuchi N, Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res 2014 115 738 750. doi: 10.1161/CIRCRESAHA.115.304563
158. Satoh K, Kagaya Y, Nakano M, Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 2006 113 1442 1450. doi: 10.1161/CIRCULATIONAHA.105.583732
159. Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, Karibe A, Kagaya Y, Ishii N, Sugamura K, Shimokawa H., Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res 2009 81 226 234. doi: 10.1093/cvr/cvn244
160. Itoh T, Nagaya N, Murakami S, Fujii T, Iwase T, Ishibashi-Ueda H, Yutani C, Yamagishi M, Kimura H, Kangawa K., C-Type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004 170 1204 1211. doi: 10.1164/rccm.200404-455OC
161. Dhaliwal JS, Casey DB, Greco AJ, Badejo AM Jr, Gallen TB, Murthy SN, Nossaman BD, Hyman AL, Kadowitz PJ., Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-Treated rats. Am J Physiol Lung Cell Mol Physiol 2007 293 L1306 L1313. doi: 10.1152/ajplung.00189.2007
162. Badejo AM Jr, Dhaliwal JS, Casey DB, Gallen TB, Greco AJ, Kadowitz PJ., Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat. Am J Physiol Lung Cell Mol Physiol 2008 295 L828 L836. doi: 10.1152/ajplung.00042.2008
163. Dhaliwal JS, Badejo AM Jr, Casey DB, Murthy SN, Kadowitz PJ., Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-Amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-Amine], a novel aminofurazan-based Rho kinase inhibitor. J Pharmacol Exp Ther 2009 330 334 341. doi: 10.1124/jpet.109.151449
164. Casey DB, Badejo AM, Dhaliwal JS, Sikora JL, Fokin A, Golwala NH, Greco AJ, Murthy SN, Nossaman BD, Hyman AL, Kadowitz PJ., Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat. Am J Physiol Heart Circ Physiol 2010 299 H184 H192. doi: 10.1152/ajpheart.00181.2009
165. Kikuchi Y, Yasuda S, Aizawa K, Tsuburaya R, Ito Y, Takeda M, Nakayama M, Ito K, Takahashi J, Shimokawa H., Enhanced Rho-kinase activity in circulating neutrophils of patients with vasospastic angina: a possible biomarker for diagnosis and disease activity assessment. J Am Coll Cardiol 2011 58 1231 1237. doi: 10.1016/j.jacc.2011.05.046
166. Nihei T, Takahashi J, Tsuburaya R, Ito Y, Shiroto T, Hao K, Takagi Y, Matsumoto Y, Nakayama M, Miyata S, Sakata Y, Ito K, Shimokawa H., Circadian variation of Rho-kinase activity in circulating leukocytes of patients with vasospastic angina. Circ J 2014 78 1183 1190
167. Saito T, Hirano M, Ide T, Ichiki T, Koibuchi N, Sunagawa K, Hirano K., Pivotal role of Rho-Associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility. Circulation 2013 127 104 114. doi: 10.1161/CIRCULATIONAHA.112.135608
168. Xie Z, Su W, Liu S, Zhao G, Esser K, Schroder EA, Lefta M, Stauss HM, Guo Z, Gong MC., Smooth-muscle BMAL1 participates in blood pressure circadian rhythm regulation. J Clin Invest 2015 125 324 336. doi: 10.1172/JCI76881
169. Soga J, Noma K, Hata T, Hidaka T, Fujii Y, Idei N, Fujimura N, Mikami S, Maruhashi T, Kihara Y, Chayama K, Kato H, Liao JK, Higashi Y, ROCK Study Group Rho-Associated kinase activity, endothelial function, and cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2011 31 2353 2359. doi: 10.1161/ATVBAHA.111.227892
170. Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A., Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002 105 1545 1547
171. Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A., Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J Am Coll Cardiol 2003 41 15 19
172. Shiroto T, Yasuda S, Tsuburaya R, Ito Y, Takahashi J, Ito K, Ishibashi-Ueda H, Shimokawa H., Role of Rho-kinase in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in pigs in vivo. J Am Coll Cardiol 2009 54 2321 2329. doi: 10.1016/j.jacc.2009.07.045
173. Aizawa K, Yasuda S, Takahashi J, Takii T, Kikuchi Y, Tsuburaya R, Ito Y, Ito K, Nakayama M, Takeda M, Shimokawa H., Involvement of rho-kinase activation in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in patients with coronary artery disease. Circ J 2012 76 2552 2560
174. Tsuburaya R, Yasuda S, Shiroto T, Ito Y, Gao JY, Aizawa K, Kikuchi Y, Ito K, Takahashi J, Ishibashi-Ueda H, Shimokawa H., Long-Term treatment with nifedipine suppresses coronary hyperconstricting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo: possible involvement of Rho-kinase pathway. Eur Heart J 2012 33 791 799. doi: 10.1093/eurheartj/ehr145
175. Satoh K, Fukumoto Y, Sugimura K, Plasma cyclophilin A is a novel biomarker for coronary artery disease. Circ J 2013 77 447 455
176. Do e Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M, Tada T, Saji K, Sugimura K, Fujita H, Hoshikawa Y, Nawata J, Kondo T, Shimokawa H., Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J 2009 73 1731 1739
177. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H., Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005 91 391 392. doi: 10.1136/hrt.2003.029470
178. Fukumoto Y, Yamada N, Matsubara H, Double-blind, placebo-controlled clinical trial with a Rho-kinase inhibitor in pulmonary arterial hypertension. Circ J 2013 77 2619 2625
179. Akama T, Dong C, Virtucio C, Freund YR, Chen D, Orr MD, Jacobs RT, Zhang YK, Hernandez V, Liu Y, Wu A, Bu W, Liu L, Jarnagin K, Plattner JJ., Discovery and structure-Activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents. Bioorg Med Chem Lett 2013 23 5870 5873. doi: 10.1016/j.bmcl.2013.08.096
180. Akama T, Dong C, Virtucio C, Sullivan D, Zhou Y, Zhang YK, Rock F, Freund Y, Liu L, Bu W, Wu A, Fan XQ, Jarnagin K., Linking phenotype to kinase: identification of a novel benzoxaborole hinge-binding motif for kinase inhibition and development of high-potency rho kinase inhibitors. J Pharmacol Exp Ther 2013 347 615 625. doi: 10.1124/jpet.113.207662