Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity (original) (raw)

1. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J. 1996;15:1885–1893. [PMC free article] [PubMed] [Google Scholar]

2. 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;270:29051–29054. doi: 10.1074/jbc.270.49.29051. [PubMed] [CrossRef] [Google Scholar]

3. 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. [PMC free article] [PubMed] [Google Scholar]

4. Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996;392:189–193. doi: 10.1016/0014-5793(96)00811-3. [PubMed] [CrossRef] [Google Scholar]

5. 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. doi: 10.1074/jbc.271.34.20246. [PubMed] [CrossRef] [Google Scholar]

6. 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. doi: 10.1074/jbc.272.19.12257. [PubMed] [CrossRef] [Google Scholar]

7. Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K. Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo. J Cell Biol. 1999;147:1023–1038. doi: 10.1083/jcb.147.5.1023. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

8. 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. doi: 10.1126/science.273.5272.245. [PubMed] [CrossRef] [Google Scholar]

9. Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol. 1998;140:647–657. doi: 10.1083/jcb.140.3.647. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. Fukata Y, Oshiro N, Kinoshita N, Kawano Y, Matsuoka Y, Bennett V, Matsuura Y, Kaibuchi K. Phosphorylation of adducin by Rho-kinase plays a crucial role in cell motility. J Cell Biol. 1999;145:347–361. doi: 10.1083/jcb.145.2.347. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

11. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999;285:895–898. doi: 10.1126/science.285.5429.895. [PubMed] [CrossRef] [Google Scholar]

12. Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K. Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem. 2000;275:3577–3582. doi: 10.1074/jbc.275.5.3577. [PubMed] [CrossRef] [Google Scholar]

13. Sumi T, Matsumoto K, Nakamura T. Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. J Biol Chem. 2001;276:670–676. doi: 10.1074/jbc.M007074200. [PubMed] [CrossRef] [Google Scholar]

14. Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003;4:446–456. doi: 10.1038/nrm1128. [PubMed] [CrossRef] [Google Scholar]

15. 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. [PubMed] [CrossRef] [Google Scholar]

16. Carbajal JM, Gratrix ML, Yu CH, Schaeffer RC., Jr ROCK mediates thrombin’s endothelial barrier dysfunction. Am J Physiol Cell Physiol. 2000;279:C195–C204. [PubMed] [Google Scholar]

17. Gavard J, Gutkind JS. Protein kinase C-related kinase and ROCK are required for thrombin-induced endothelial cell permeability downstream from Galpha12/13 and Galpha11/q. J Biol Chem. 2008;283:29888–29896. doi: 10.1074/jbc.M803880200. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

18. McKenzie JA, Ridley AJ. Roles of Rho/ROCK and MLCK in TNF-alpha-induced changes in endothelial morphology and permeability. J Cell Physiol. 2007;213:221–228. doi: 10.1002/jcp.21114. [PubMed] [CrossRef] [Google Scholar]

19. van Nieuw Amerongen GP, Beckers CM, Achekar ID, Zeeman S, Musters RJ, van Hinsbergh VW. Involvement of Rho kinase in endothelial barrier maintenance. Arterioscler Thromb Vasc Biol. 2007;27:2332–2339. doi: 10.1161/ATVBAHA.107.152322. [PubMed] [CrossRef] [Google Scholar]

20. van Nieuw Amerongen GP, Musters RJ, Eringa EC, Sipkema P, van Hinsbergh VW. Thrombin-induced endothelial barrier disruption in intact microvessels: role of RhoA/Rho kinase-myosin phosphatase axis. Am J Physiol Cell Physiol. 2008;294:C1234–C1241. doi: 10.1152/ajpcell.00551.2007. [PubMed] [CrossRef] [Google Scholar]

21. 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. [PubMed] [Google Scholar]

22. Vandenbroucke E, Mehta D, Minshall R, Malik AB. Regulation of endothelial junctional permeability. Ann N Y Acad Sci. 2008;1123:134–145. doi: 10.1196/annals.1420.016. [PubMed] [CrossRef] [Google Scholar]

23. Shimizu Y, Thumkeo D, Keel J, Ishizaki T, Oshima H, Oshima M, Noda Y, Matsumura F, Taketo MM, Narumiya S. ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol. 2005;168:941–953. doi: 10.1083/jcb.200411179. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

24. Thumkeo D, Keel J, Ishizaki T, Hirose M, Nonomura K, Oshima H, Oshima M, Taketo MM, Narumiya S. Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol Cell Biol. 2003;23:5043–5055. doi: 10.1128/MCB.23.14.5043-5055.2003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

25. Thumkeo D, Shimizu Y, Sakamoto S, Yamada S, Narumiya S. ROCK-I and ROCK-II cooperatively regulate closure of eyelid and ventral body wall in mouse embryo. Genes Cells. 2005;10:825–834. doi: 10.1111/j.1365-2443.2005.00882.x. [PubMed] [CrossRef] [Google Scholar]

26. Yoneda A, Multhaupt HA, Couchman JR. The Rho kinases I and II regulate different aspects of myosin II activity. J Cell Biol. 2005;170:443–453. doi: 10.1083/jcb.200412043. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

27. Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351:95–105. doi: 10.1042/0264-6021:3510095. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

28. Chen YT, Bannister TD, Weiser A, Griffin E, Lin L, Ruiz C, Cameron MD, Schurer S, Duckett D, Schroter T, LoGrasso P, Feng Y. Chroman-3-amides as potent Rho kinase inhibitors. Bioorgan Med Chem Lett. 2008;18:6406–6409. doi: 10.1016/j.bmcl.2008.10.080. [PubMed] [CrossRef] [Google Scholar]

29. Feng Y, Yin Y, Weiser A, Griffin E, Cameron MD, Lin L, Ruiz C, Schurer SC, Inoue T, Rao PV, Schroter T, Lograsso P. Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. J Med Chem. 2008;51:6642–6645. doi: 10.1021/jm800986w. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

30. Goodman KB, Cui H, Dowdell SE, Gaitanopoulos DE, Ivy RL, Sehon CA, Stavenger RA, Wang GZ, Viet AQ, Xu W, Ye G, Semus SF, Evans C, Fries HE, Jolivette LJ, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Bentley R, Doe CP, Hu E, Lee D. Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors. J Med Chem. 2007;50:6–9. doi: 10.1021/jm0609014. [PubMed] [CrossRef] [Google Scholar]

31. Lohn M, Plettenburg O, Ivashchenko Y, Kannt A, Hofmeister A, Kadereit D, Schaefer M, Linz W, Kohlmann M, Herbert JM, Janiak P, O’Connor SE, Ruetten H. Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. Hypertension. 2009;54:676–683. doi: 10.1161/HYPERTENSIONAHA.109.134353. [PubMed] [CrossRef] [Google Scholar]

32. Nakajima M, Hayashi K, Katayama K, Amano Y, Egi Y, Uehata M, Goto N, Kondo T. Wf-536 prevents tumor metastasis by inhibiting both tumor motility and angiogenic actions. Eur J Pharmacol. 2003;459:113–120. doi: 10.1016/S0014-2999(02)02869-8. [PubMed] [CrossRef] [Google Scholar]

33. Sessions EH, Yin Y, Bannister TD, Weiser A, Griffin E, Pocas J, Cameron MD, Ruiz C, Lin L, Schurer SC, Schroter T, LoGrasso P, Feng Y. Benzimidazole- and benzoxazole-based inhibitors of Rho kinase. Bioorgan Med Chem Lett. 2008;18:6390–6393. doi: 10.1016/j.bmcl.2008.10.095. [PubMed] [CrossRef] [Google Scholar]

34. Stavenger RA, Cui H, Dowdell SE, Franz RG, Gaitanopoulos DE, Goodman KB, Hilfiker MA, Ivy RL, Leber JD, Marino JP, Jr, Oh HJ, Viet AQ, Xu W, Ye G, Zhang D, Zhao Y, Jolivette LJ, Head MS, Semus SF, Elkins PA, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Doe CP, Bentley R, Chen ZX, Hu E, Lee D. Discovery of aminofurazan-azabenzimidazoles as inhibitors of Rho-kinase with high kinase selectivity and antihypertensive activity. J Med Chem. 2007;50:2–5. doi: 10.1021/jm060873p. [PubMed] [CrossRef] [Google Scholar]

35. Tanihara H, Inatani M, Honjo M, Tokushige H, Azuma J, Araie M. Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch Ophthalmol. 2008;126:309–315. doi: 10.1001/archophthalmol.2007.76. [PubMed] [CrossRef] [Google Scholar]

36. Tokushige H, Inatani M, Nemoto S, Sakaki H, Katayama K, Uehata M, Tanihara H. Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest Ophthalmol Vis Sci. 2007;48:3216–3222. doi: 10.1167/iovs.05-1617. [PubMed] [CrossRef] [Google Scholar]

37. Whitlock NA, Harrison B, Mixon T, Yu XQ, Wilson A, Gerhardt B, Eberhart DE, Abuin A, Rice DS. Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J Ocul Pharmacol Therap. 2009;25:187–194. doi: 10.1089/jop.2008.0142. [PubMed] [CrossRef] [Google Scholar]

38. Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009;104:531–540. doi: 10.1161/CIRCRESAHA.108.188524. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

39. Riento K, Guasch RM, Garg R, Jin B, Ridley AJ. RhoE binds to ROCK I and inhibits downstream signaling. Mol Cell Biol. 2003;23:4219–4229. doi: 10.1128/MCB.23.12.4219-4229.2003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

40. Garg R, Riento K, Keep N, Morris JD, Ridley AJ. N-terminus-mediated dimerization of ROCK-I is required for RhoE binding and actin reorganization. Biochem J. 2008;411:407–414. doi: 10.1042/BJ20071342. [PubMed] [CrossRef] [Google Scholar]

41. Komander D, Garg R, Wan PT, Ridley AJ, Barford D. Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure. EMBO J. 2008;27:3175–3185. doi: 10.1038/emboj.2008.226. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

42. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol. 2001;3:339–345. doi: 10.1038/35070009. [PubMed] [CrossRef] [Google Scholar]

43. Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J. Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol. 2001;3:346–352. doi: 10.1038/35070019. [PubMed] [CrossRef] [Google Scholar]

44. Sebbagh M, Hamelin J, Bertoglio J, Solary E, Breard J. Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med. 2005;201:465–471. doi: 10.1084/jem.20031877. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Zhang Y, Li X, Qi J, Wang J, Liu X, Zhang H, Lin SC, Meng A. Rock2 controls TGF{beta} signaling and inhibits mesoderm induction in zebrafish embryos. J Cell Sci. 2009;122:2197–2207. doi: 10.1242/jcs.040659. [PubMed] [CrossRef] [Google Scholar]

46. Ongusaha PP, Qi HH, Raj L, Kim YB, Aaronson SA, Davis RJ, Shi Y, Liao JK, Lee SW (2008) Identification of ROCK1 as an upstream activator of the JIP-3 to JNK signaling axis in response to UVB damage. Sci Signal 1, ra14 [PMC free article] [PubMed]

47. Shea KF, Wells CM, Garner AP, Jones GE. ROCK1 and LIMK2 interact in spread but not blebbing cancer cells. PLoS ONE. 2008;3:e3398. doi: 10.1371/journal.pone.0003398. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

48. Zhang YM, Bo J, Taffet GE, Chang J, Shi J, Reddy AK, Michael LH, Schneider MD, Entman ML, Schwartz RJ, Wei L. Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. FASEB J. 2006;20:916–925. doi: 10.1096/fj.05-5129com. [PubMed] [CrossRef] [Google Scholar]

49. Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1 ± haploinsufficient mice. Circulation. 2005;112:2959–2965. [PMC free article] [PubMed] [Google Scholar]

50. Wong CC, Wong CM, Tung EK, Man K, Ng IO. Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology. 2009;49:1583–1594. doi: 10.1002/hep.22836. [PubMed] [CrossRef] [Google Scholar]

51. Vishnubhotla R, Sun S, Huq J, Bulic M, Ramesh A, Guzman G, Cho M, Glover SC. ROCK-II mediates colon cancer invasion via regulation of MMP-2 and MMP-13 at the site of invadopodia as revealed by multiphoton imaging. Lab Invest. 2007;87:1149–1158. doi: 10.1038/labinvest.3700674. [PubMed] [CrossRef] [Google Scholar]

52. Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H. Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res. 2003;9:2632–2641. [PubMed] [Google Scholar]

53. Lane J, Martin TA, Watkins G, Mansel RE, Jiang WG. The expression and prognostic value of ROCK I and ROCK II and their role in human breast cancer. Int J Oncol. 2008;33:585–593. [PubMed] [Google Scholar]

54. Lin SL, Chang D, Ying SY. Hyaluronan stimulates transformation of androgen-independent prostate cancer. Carcinogenesis. 2007;28:310–320. doi: 10.1093/carcin/bgl134. [PubMed] [CrossRef] [Google Scholar]

55. Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E, Ostroff GR, Czech MP. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature. 2009;458:1180–1184. doi: 10.1038/nature07774. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

56. Medarova Z, Pham W, Farrar C, Petkova V, Moore A. In vivo imaging of siRNA delivery and silencing in tumors. Nat Med. 2007;13:372–377. doi: 10.1038/nm1486. [PubMed] [CrossRef] [Google Scholar]

57. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing’s sarcoma. Cancer Res. 2005;65:8984–8992. doi: 10.1158/0008-5472.CAN-05-0565. [PubMed] [CrossRef] [Google Scholar]

58. Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P, Manjunath N. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448:39–43. doi: 10.1038/nature05901. [PubMed] [CrossRef] [Google Scholar]

59. Kast R, Schirok H, Figueroa-Perez S, Mittendorf J, Gnoth MJ, Apeler H, Lenz J, Franz JK, Knorr A, Hutter J, Lobell M, Zimmermann K, Munter K, Augstein KH, Ehmke H, Stasch JP. Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase. Br J Pharmacol. 2007;152:1070–1080. doi: 10.1038/sj.bjp.0707484. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. Schirok H, Kast R, Figueroa-Perez S, Bennabi S, Gnoth MJ, Feurer A, Heckroth H, Thutewohl M, Paulsen H, Knorr A, Hutter J, Lobell M, Munter K, Geiss V, Ehmke H, Lang D, Radtke M, Mittendorf J, Stasch JP. Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors. ChemMedChem. 2008;3:1893–1904. doi: 10.1002/cmdc.200800211. [PubMed] [CrossRef] [Google Scholar]

61. Shifrin V, Annand RR, Flusberg D, McGonigle S, Wong E, Paradise E, Bartolozzi A, Ram S, Foudoulakis H, Kirk B, Chesworth R, Riesinger S, Grogan M, Tsaioun K, Malchoff A, Ter-Ovanesyan E, Waechter R, Duffy D, Kim E, Schueller O, Campbell S (2005) Effects of SLx-2119, a novel small molecule inhibitor of Rho-associated kinase ROCK (ROK), on growth of human tumor xenografts in nude mice. AACR Meeting Abstracts 2005, 158

62. Boerma M, Fu Q, Wang J, Loose DS, Bartolozzi A, Ellis JL, McGonigle S, Paradise E, Sweetnam P, Fink LM, Vozenin-Brotons MC, Hauer-Jensen M. Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin. Blood Coagul Fibrinolysis. 2008;19:709–718. doi: 10.1097/MBC.0b013e32830b2891. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Schueller O, Tong W, Ferkany JW, Sweetnam P (2006) Abstract 1216: Selective ROCK 2 inhibition attenuates arterial plaque formation in an ApoE knockout mouse model. Circulation 114, II_228-b-

64. Seasholtz TM, Wessel J, Rao F, Rana BK, Khandrika S, Kennedy BP, Lillie EO, Ziegler MG, Smith DW, Schork NJ, Brown JH, O’Connor DT. Rho kinase polymorphism influences blood pressure and systemic vascular resistance in human twins: role of heredity. Hypertension. 2006;47:937–947. doi: 10.1161/01.HYP.0000217364.45622.f0. [PubMed] [CrossRef] [Google Scholar]

65. Rankinen T, Church T, Rice T, Markward N, Blair SN, Bouchard C. A major haplotype block at the rho-associated kinase 2 locus is associated with a lower risk of hypertension in a recessive manner: the HYPGENE study. Hypertens Res. 2008;31:1651–1657. doi: 10.1291/hypres.31.1651. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension. 2001;38:1307–1310. doi: 10.1161/hy1201.096541. [PubMed] [CrossRef] [Google Scholar]

67. 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

68. Honjo M, Inatani M, Kido N, Sawamura T, Yue BY, Honda Y, Tanihara H. Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes. Arch Ophthalmol. 2001;119:1171–1178. [PubMed] [Google Scholar]

69. Honjo M, Tanihara H, Inatani M, Kido N, Sawamura T, Yue BY, Narumiya S, Honda Y. Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci. 2001;42:137–144. [PubMed] [Google Scholar]

70. Waki M, Yoshida Y, Oka T, Azuma M. Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase. Curr Eye Res. 2001;22:470–474. doi: 10.1076/ceyr.22.6.470.5489. [PubMed] [CrossRef] [Google Scholar]

71. Rao PV, Deng PF, Kumar J, Epstein DL. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest Ophthalmol Vis Sci. 2001;42:1029–1037. [PubMed] [Google Scholar]

72. Tian B, Kaufman PL. Effects of the Rho kinase inhibitor Y-27632 and the phosphatase inhibitor calyculin A on outflow facility in monkeys. Exp Eye Res. 2005;80:215–225. doi: 10.1016/j.exer.2004.09.002. [PubMed] [CrossRef] [Google Scholar]

73. Chan CC, Khodarahmi K, Liu J, Sutherland D, Oschipok LW, Steeves JD, Tetzlaff W. Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury. Exp Neurol. 2005;196:352–364. doi: 10.1016/j.expneurol.2005.08.011. [PubMed] [CrossRef] [Google Scholar]

74. Fournier AE, Takizawa BT, Strittmatter SM. Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci. 2003;23:1416–1423. [PMC free article] [PubMed] [Google Scholar]

75. Hara M, Takayasu M, Watanabe K, Noda A, Takagi T, Suzuki Y, Yoshida J. Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats. J Neurosurg. 2000;93:94–101. [PubMed] [Google Scholar]

76. Tanaka H, Yamashita T, Yachi K, Fujiwara T, Yoshikawa H, Tohyama M. Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience. 2004;127:155–164. doi: 10.1016/j.neuroscience.2004.05.010. [PubMed] [CrossRef] [Google Scholar]

77. Zhou Y, Su Y, Li B, Liu F, Ryder JW, Wu X, Gonzalez-DeWhitt PA, Gelfanova V, Hale JE, May PC, Paul SM, Ni B. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho. Science. 2003;302:1215–1217. doi: 10.1126/science.1090154. [PubMed] [CrossRef] [Google Scholar]

78. Bauer PO, Wong HK, Oyama F, Goswami A, Okuno M, Kino Y, Miyazaki H, Nukina N. Inhibition of Rho kinases enhances the degradation of mutant huntingtin. J Biol Chem. 2009;284:13153–13164. doi: 10.1074/jbc.M809229200. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

79. Nakajima M, Hayashi K, Egi Y, Katayama K, Amano Y, Uehata M, Ohtsuki M, Fujii A, Oshita K, Kataoka H, Chiba K, Goto N, Kondo T. Effect of Wf-536, a novel ROCK inhibitor, against metastasis of B16 melanoma. Cancer Chemother Pharmacol. 2003;52:319–324. doi: 10.1007/s00280-003-0641-9. [PubMed] [CrossRef] [Google Scholar]

80. Somlyo AV, Phelps C, Dipierro C, Eto M, Read P, Barrett M, Gibson JJ, Burnitz MC, Myers C, Somlyo AP. Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants. FASEB J. 2003;17:223–234. doi: 10.1096/fj.02-0655com. [PubMed] [CrossRef] [Google Scholar]

81. Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP. Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem Biophys Res Commun. 2000;269:652–659. doi: 10.1006/bbrc.2000.2343. [PubMed] [CrossRef] [Google Scholar]

82. Takamura M, Sakamoto M, Genda T, Ichida T, Asakura H, Hirohashi S. Inhibition of intrahepatic metastasis of human hepatocellular carcinoma by Rho-associated protein kinase inhibitor Y-27632. Hepatology. 2001;33:577–581. doi: 10.1053/jhep.2001.22652. [PubMed] [CrossRef] [Google Scholar]

83. Ying H, Biroc SL, Li WW, Alicke B, Xuan JA, Pagila R, Ohashi Y, Okada T, Kamata Y, Dinter H. The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models. Mol Cancer Ther. 2006;5:2158–2164. doi: 10.1158/1535-7163.MCT-05-0440. [PubMed] [CrossRef] [Google Scholar]

84. Nagatoya K, Moriyama T, Kawada N, Takeji M, Oseto S, Murozono T, Ando A, Imai E, Hori M. Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 2002;61:1684–1695. doi: 10.1046/j.1523-1755.2002.00328.x. [PubMed] [CrossRef] [Google Scholar]

85. Kanda T, Wakino S, Hayashi K, Homma K, Ozawa Y, Saruta T. Effect of fasudil on Rho-kinase and nephropathy in subtotally nephrectomized spontaneously hypertensive rats. Kidney Int. 2003;64:2009–2019. doi: 10.1046/j.1523-1755.2003.00300.x. [PubMed] [CrossRef] [Google Scholar]

86. Kikuchi Y, Yamada M, Imakiire T, Kushiyama T, Higashi K, Hyodo N, Yamamoto K, Oda T, Suzuki S, Miura S. A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J Endocrinol. 2007;192:595–603. doi: 10.1677/JOE-06-0045. [PubMed] [CrossRef] [Google Scholar]

87. Nishikimi T, Akimoto K, Wang X, Mori Y, Tadokoro K, Ishikawa Y, Shimokawa H, Ono H, Matsuoka H. Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats. J Hypertens. 2004;22:1787–1796. doi: 10.1097/00004872-200409000-00024. [PubMed] [CrossRef] [Google Scholar]

88. Nishikimi T, Koshikawa S, Ishikawa Y, Akimoto K, Inaba C, Ishimura K, Ono H, Matsuoka H. Inhibition of Rho-kinase attenuates nephrosclerosis and improves survival in salt-loaded spontaneously hypertensive stroke-prone rats. J Hypertens. 2007;25:1053–1063. doi: 10.1097/HJH.0b013e3280825440. [PubMed] [CrossRef] [Google Scholar]

89. Satoh S, Yamaguchi T, Hitomi A, Sato N, Shiraiwa K, Ikegaki I, Asano T, Shimokawa H. Fasudil attenuates interstitial fibrosis in rat kidneys with unilateral ureteral obstruction. Eur J Pharmacol. 2002;455:169–174. doi: 10.1016/S0014-2999(02)02619-5. [PubMed] [CrossRef] [Google Scholar]

90. Kolavennu V, Zeng L, Peng H, Wang Y, Danesh FR. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes. 2008;57:714–723. doi: 10.2337/db07-1241. [PubMed] [CrossRef] [Google Scholar]

91. Kanda T, Wakino S, Homma K, Yoshioka K, Tatematsu S, Hasegawa K, Takamatsu I, Sugano N, Hayashi K, Saruta T. Rho-kinase as a molecular target for insulin resistance and hypertension. FASEB J. 2006;20:169–171. [PubMed] [Google Scholar]

92. Chitaley K, Wingard CJ, Clinton Webb R, Branam H, Stopper VS, Lewis RW, Mills TM. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med. 2001;7:119–122. doi: 10.1038/83258. [PubMed] [CrossRef] [Google Scholar]

93. Rajasekaran M, White S, Baquir A, Wilkes N. Rho-kinase inhibition improves erectile function in aging male Brown-Norway rats. J Androl. 2005;26:182–188. [PubMed] [Google Scholar]

94. Wingard CJ, Johnson JA, Holmes A, Prikosh A. Improved erectile function after Rho-kinase inhibition in a rat castrate model of erectile dysfunction. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1572–R1579. [PubMed] [Google Scholar]

95. Teixeira CE, Ying Z, Webb RC. Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis. J Pharmacol Exp Ther. 2005;315:155–162. doi: 10.1124/jpet.105.086041. [PubMed] [CrossRef] [Google Scholar]