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Rho-Kinase in Development and Heart Failure: Insights From Genetic Models

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Abstract

Rho-kinase (ROCK) belongs to the AGC (protein kinase A/protein kinase G/protein kinase C, PKA/PKG/PKC) family of serine/threonine kinases and is a major downstream effector of small GTPase RhoA. Rho-kinase is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be functionally redundant, based largely on the major common activators, the high degree of homology within the kinase domain, and studies from overexpression with kinase constructs and chemical inhibitors (e.g., Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiologic, and pathophysiologic functions of the two ROCK isoforms. This review focuses on the current understanding of ROCK isoform biology, with a particular emphasis on their functions in mouse development and the pathogenesis of heart failure.

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References

  1. Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn GW II (1998) Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci USA 95:10140–10145

    Article  PubMed  CAS  Google Scholar 

  2. Amano M, Chihara K, Nakamura N, Kaneko T, Matsuura Y, Kaibuchi K (1999) The COOH terminus of rho-kinase negatively regulates rho-kinase activity. J Biol Chem 274:32418–32424

    Article  PubMed  CAS  Google Scholar 

  3. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K (1996) Phosphorylation and activation of myosin by rho-associated kinase (rho-kinase). J Biol Chem 271:20246–20249

    Article  PubMed  CAS  Google Scholar 

  4. Amano M, Nakayama M, Kaibuchi K (2010) Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity. Cytoskeleton Hoboken 67:545–554

    Article  PubMed  CAS  Google Scholar 

  5. Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H (1987) Mechanism of action of a novel antivasospasm drug, HA1077. J Pharmacol Exp Ther 241:1033–1040

    PubMed  CAS  Google Scholar 

  6. 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 (2008) Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of rho-kinase or atorvastatin. Blood Coagul Fibrinolysis 19:709–718

    Article  PubMed  CAS  Google Scholar 

  7. Breitenlechner C, Gassel M, Hidaka H, Kinzel V, Huber R, Engh RA, Bossemeyer D (2003) Protein kinase A in complex with rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity. Structure 11:1595–1607

    Article  PubMed  CAS  Google Scholar 

  8. Bryan BA, Dennstedt E, Mitchell DC, Walshe TE, Noma K, Loureiro R, Saint-Geniez M, Campaigniac JP, Liao JK, D’Amore PA (2010) RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis. FASEB J 24:3186–3195

    Article  PubMed  CAS  Google Scholar 

  9. Chang J, Xie M, Shah VR, Schneider MD, Entman ML, Wei L, Schwartz RJ (2006) Activation of rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosis. Proc Natl Acad Sci USA 103:14495–14500

    Article  PubMed  CAS  Google Scholar 

  10. Chen XQ, Tan I, Ng CH, Hall C, Lim L, Leung T (2002) Characterization of rhoA-binding kinase ROKalpha implication of the pleckstrin homology domain in ROKalpha function using region-specific antibodies. J Biol Chem 277:12680–12688

    Article  PubMed  CAS  Google Scholar 

  11. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345

    Article  PubMed  CAS  Google Scholar 

  12. Davies SP, Reddy H, Caivano M, Cohen P (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105

    Article  PubMed  CAS  Google Scholar 

  13. Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, Epstein ND (2001) The overall pattern of cardiac contraction depends on a spatial gradient of myosin regulatory light chain phosphorylation. Cell 107:631–641

    Article  PubMed  CAS  Google Scholar 

  14. Del Re DP, Miyamoto S, Brown JH (2007) RhoA/rho-kinase upregulates Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis. J Biol Chem 282:8069–8078

    Article  PubMed  CAS  Google Scholar 

  15. Del Re DP, Miyamoto S, Brown JH (2008) Focal adhesion kinase as a rhoA-activable signaling scaffold mediating Akt activation and cardiomyocyte protection. J Biol Chem 283:35622–35629

    Article  PubMed  CAS  Google Scholar 

  16. Dong M, Yan BP, Liao JK, Lam YY, Yip GW, Yu CM (2010) Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today 15:622–629

    Article  PubMed  CAS  Google Scholar 

  17. Duffy P, Schmandke A, Schmandke A, Sigworth J, Narumiya S, Cafferty WB, Strittmatter SM (2009) Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord. J Neurosci 29:15266–15276

    Article  PubMed  CAS  Google Scholar 

  18. Feng J, Ito M, Kureishi Y, Ichikawa K, Amano M, Isaka N, Okawa K, Iwamatsu A, Kaibuchi K, Hartshorne DJ, Nakano T (1999) Rho-associated kinase of chicken gizzard smooth muscle. J Biol Chem 274:3744–3752

    Article  PubMed  CAS  Google Scholar 

  19. Fu P, Liu F, Su S, Wang W, Huang XR, Entman ML, Schwartz RJ, Wei L, Lan HY (2006) Signaling mechanism of renal fibrosis in unilateral ureteral obstructive kidney disease in ROCK1 knockout mice. J Am Soc Nephrol 17:3105–3114

    Article  PubMed  CAS  Google Scholar 

  20. Fu X, Gong MC, Jia T, Somlyo AV, Somlyo AP (1998) The effects of the rho-kinase inhibitor Y-27632 on arachidonic acid-, GTPgammaS-, and phorbol ester-induced Ca2+-sensitization of smooth muscle. FEBS Lett 440:183–187

    Article  PubMed  CAS  Google Scholar 

  21. Fujisawa K, Fujita A, Ishizaki T, Saito Y, Narumiya S (1996) Identification of the rho-binding domain of p160ROCK, a rho-associated coiled-coil containing protein kinase. J Biol Chem 271:23022–23028

    Article  PubMed  CAS  Google Scholar 

  22. Fukata Y, Oshiro N, Kinoshita N, Kawano Y, Matsuoka Y, Bennett V, Matsuura Y, Kaibuchi K (1999) Phosphorylation of adducin by rho-kinase plays a crucial role in cell motility. J Cell Biol 145:347–361

    Article  PubMed  CAS  Google Scholar 

  23. Fukui S, Fukumoto Y, Suzuki J, Saji K, Nawata J, Tawara S, Shinozaki T, Kagaya Y, Shimokawa H (2008) Long-term inhibition of rho-kinase ameliorates diastolic heart failure in hypertensive rats. J Cardiovasc Pharmacol 51:317–326

    Article  PubMed  CAS  Google Scholar 

  24. Grimm M, Haas P, Willipinski-Stapelfeldt B, Zimmermann WH, Rau T, Pantel K, Weyand M, Eschenhagen T (2005) Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium. Cardiovasc Res 65:211–220

    Article  PubMed  CAS  Google Scholar 

  25. Hahmann C, Schroeter T (2010) Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity. Cell Mol Life Sci 67:171–177

    Article  PubMed  CAS  Google Scholar 

  26. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, Kaibuchi K, Takeshita A (2004) Long-term inhibition of rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation 109:2234–2239

    Article  PubMed  CAS  Google Scholar 

  27. Haudek SB, Gupta D, Dewald O, Schwarz RJ, Wei L, Trial J, Entman ML (2009) Rho-kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation. Cardiovasc Res 83:511–518

    Article  PubMed  CAS  Google Scholar 

  28. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A (2003) 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 93:767–775

    Article  PubMed  CAS  Google Scholar 

  29. Inaba N, Ishizawa S, Kimura M, Fujioka K, Watanabe M, Shibasaki T, Manome Y (2010) Effect of inhibition of the ROCK isoform on RT2 malignant glioma cells. Anticancer Res 30:3509–3514

    PubMed  CAS  Google Scholar 

  30. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S (1996) The small GTP-binding protein rho binds to and activates a 160-kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. Embo J 15:1885–1893

    PubMed  CAS  Google Scholar 

  31. Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M, Narumiya S (2000) Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol 57:976–983

    PubMed  CAS  Google Scholar 

  32. Kawabata S, Usukura J, Morone N, Ito M, Iwamatsu A, Kaibuchi K, Amano M (2004) Interaction of rho-kinase with myosin II at stress fibres. Genes Cells 9:653–660

    Article  PubMed  CAS  Google Scholar 

  33. Kawano Y, Fukata Y, Oshiro N, Amano M, Nakamura T, Ito M, Matsumura F, Inagaki M, Kaibuchi K (1999) Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by rho-kinase in vivo. J Cell Biol 147:1023–1038

    Article  PubMed  CAS  Google Scholar 

  34. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Regulation of myosin phosphatase by rho and rho-associated kinase (rho-kinase). Science 273:245–248

    Article  PubMed  CAS  Google Scholar 

  35. Kobayashi N, Horinaka S, Mita S, Nakano S, Honda T, Yoshida K, Kobayashi T, Matsuoka H (2002) Critical role of rho-kinase pathway for cardiac performance and remodeling in failing rat hearts. Cardiovasc Res 55:757–767

    Article  PubMed  CAS  Google Scholar 

  36. Kureishi Y, Kobayashi S, Amano M, Kimura K, Kanaide H, Nakano T, Kaibuchi K, Ito M (1997) rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem 272:12257–12260

    Article  PubMed  CAS  Google Scholar 

  37. Lee DH, Shi J, Jeoung NH, Kim MS, Zabolotny JM, Lee SW, White MF, Wei L, Kim YB (2009) Targeted disruption of ROCK1 causes insulin resistance in vivo. J Biol Chem 284:11776–11780

    Article  PubMed  CAS  Google Scholar 

  38. Leung T, Chen XQ, Manser E, Lim L (1996) 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 16:5313–5327

    PubMed  CAS  Google Scholar 

  39. Lock FE, Hotchin NA (2009) Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One 4:e8190

    Article  PubMed  Google Scholar 

  40. Loirand G, Pacaud P (2010) The role of rho protein signaling in hypertension. Nat Rev Cardiol 7:637–647

    Article  PubMed  CAS  Google Scholar 

  41. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S (1999) Signaling from rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285:895–898

    Article  PubMed  CAS  Google Scholar 

  42. Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein rho. Embo J 15:2208–2216

    PubMed  CAS  Google Scholar 

  43. Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S, Tsukita S (1998) Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol 140:647–657

    Article  PubMed  CAS  Google Scholar 

  44. Miyamoto S, Del Re DP, Xiang SY, Zhao X, Florholmen G, Brown JH (2010) Revisited and revised: is rhoA always a villain in cardiac pathophysiology? J Cardiovasc Transl Res 3:330–343

    Article  PubMed  Google Scholar 

  45. Mong PY, Wang Q (2009) Activation of rho-kinase isoforms in lung endothelial cells during inflammation. J Immunol 182:2385–2394

    Article  PubMed  CAS  Google Scholar 

  46. Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (1996) ROCK-I and ROCK-II, two isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392:189–193

    Article  PubMed  CAS  Google Scholar 

  47. Noguchi M, Hosoda K, Fujikura J, Fujimoto M, Iwakura H, Tomita T, Ishii T, Arai N, Hirata M, Ebihara K, Masuzaki H, Itoh H, Narumiya S, Nakao K (2007) Genetic and pharmacological inhibition of rho-associated kinase II enhances adipogenesis. J Biol Chem 282:29574–29583

    Article  PubMed  CAS  Google Scholar 

  48. Noma K, Rikitake Y, Oyama N, Yan G, Alcaide P, Liu PY, Wang H, Ahl D, Sawada N, Okamoto R, Hiroi Y, Shimizu K, Luscinskas FW, Sun J, Liao JK (2008) ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest 118:1632–1644

    Article  PubMed  CAS  Google Scholar 

  49. Nunes KP, Rigsby CS, Webb RC (2010) RhoA/rho-kinase and vascular diseases: what is the link? Cell Mol Life Sci 67:3823–3836

    Article  PubMed  CAS  Google Scholar 

  50. Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K (2000) Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem 275:3577–3582

    Article  PubMed  CAS  Google Scholar 

  51. 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

    Article  PubMed  Google Scholar 

  52. Phrommintikul A, Tran L, Kompa A, Wang B, Adrahtas A, Cantwell D, Kelly DJ, Krum H (2008) Effects of a rho-kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction. Am J Physiol Heart Circ Physiol 294:H1804–H1814

    Article  PubMed  CAS  Google Scholar 

  53. Pinner S, Sahai E (2008) PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by rhoE. Nat Cell Biol 10:127–137

    Article  PubMed  CAS  Google Scholar 

  54. Rajashree R, Blunt BC, Hofmann PA (2005) Modulation of myosin phosphatase targeting subunit and protein phosphatase 1 in the heart. Am J Physiol Heart Circ Physiol 289:H1736–H1743

    Article  PubMed  CAS  Google Scholar 

  55. Riento K, Guasch RM, Garg R, Jin B, Ridley AJ (2003) RhoE binds to ROCK I and inhibits downstream signaling. Mol Cell Biol 23:4219–4229

    Article  PubMed  CAS  Google Scholar 

  56. Riento K, Totty N, Villalonga P, Garg R, Guasch R, Ridley AJ (2005) RhoE function is regulated by ROCK I-mediated phosphorylation. Embo J 24:1170–1180

    Article  PubMed  CAS  Google Scholar 

  57. Rikitake Y, Oyama N, Wang CY, Noma K, Satoh M, Kim HH, Liao JK (2005) Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1+/− haploinsufficient mice. Circulation 112:2959–2965

    PubMed  CAS  Google Scholar 

  58. Satoh S, Ueda Y, Koyanagi M, Kadokami T, Sugano M, Yoshikawa Y, Makino N (2003) Chronic inhibition of rho-kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure. J Mol Cell Cardiol 35:59–70

    Article  PubMed  CAS  Google Scholar 

  59. Sebbagh M, Hamelin J, Bertoglio J, Solary E, Breard J (2005) Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med 201:465–471

    Article  PubMed  CAS  Google Scholar 

  60. Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J (2001) Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 3:346–352

    Article  PubMed  CAS  Google Scholar 

  61. Shi J, Wei L (2007) Rho-kinase in the regulation of cell death and survival. Arch Immunol Ther Exp Warsz 55:61–75

    Article  PubMed  Google Scholar 

  62. Shi J, Zhang YW, Summers LJ, Dorn GW II, Wei L (2008) Disruption of ROCK1 gene attenuates cardiac dilation and improves contractile function in pathological cardiac hypertrophy. J Mol Cell Cardiol 44:551–560

    Article  PubMed  CAS  Google Scholar 

  63. Shi J, Zhang YW, Yang Y, Zhang L, Wei L (2010) ROCK1 plays an essential role in the transition from cardiac hypertrophy to failure in mice. J Mol Cell Cardiol 49:819–828

    Article  PubMed  CAS  Google Scholar 

  64. Shimada H, Rajagopalan LE (2010) Rho-kinase-2 activation in human endothelial cells drives lysophosphatidic acid-mediated expression of cell adhesion molecules via NF-kappaB p65. J Biol Chem 285:12536–12542

    Article  PubMed  CAS  Google Scholar 

  65. Shimizu Y, Thumkeo D, Keel J, Ishizaki T, Oshima H, Oshima M, Noda Y, Matsumura F, Taketo MM, Narumiya S (2005) ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol 168:941–953

    Article  PubMed  CAS  Google Scholar 

  66. Shirao S, Kashiwagi S, Sato M, Miwa S, Nakao F, Kurokawa T, Todoroki-Ikeda N, Mogami K, Mizukami Y, Kuriyama S, Haze K, Suzuki M, Kobayashi S (2002) Sphingosylphosphorylcholine is a novel messenger for rho-kinase-mediated Ca2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C. Circ Res 91:112–119

    Article  PubMed  CAS  Google Scholar 

  67. Small EM, Thatcher JE, Sutherland LB, Kinoshita H, Gerard RD, Richardson JA, Dimaio JM, Sadek H, Kuwahara K, Olson EN (2010) Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ Res 107:294–304

    Article  PubMed  CAS  Google Scholar 

  68. Sumi T, Matsumoto K, Nakamura T (2001) Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a rho-dependent protein kinase. J Biol Chem 276:670–676

    Article  PubMed  CAS  Google Scholar 

  69. Thumkeo D, Keel J, Ishizaki T, Hirose M, Nonomura K, Oshima H, Oshima M, Taketo MM, Narumiya S (2003) Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol Cell Biol 23:5043–5055

    Article  PubMed  CAS  Google Scholar 

  70. Thumkeo D, Shimizu Y, Sakamoto S, Yamada S, Narumiya S (2005) ROCK-I and ROCK-II cooperatively regulate closure of eyelid and ventral body wall in mouse embryo. Genes Cells 10:825–834

    Article  PubMed  CAS  Google Scholar 

  71. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S (1997) Calcium sensitization of smooth muscle mediated by a rho-associated protein kinase in hypertension. Nature 389:990–994

    Article  PubMed  CAS  Google Scholar 

  72. Vahebi S, Kobayashi T, Warren CM, de Tombe PP, Solaro RJ (2005) Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin. Circ Res 96:740–747

    Article  PubMed  CAS  Google Scholar 

  73. Vemula S, Shi J, Hanneman P, Wei L, Kapur R (2009) ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Blood 115:1785–1796

    Article  PubMed  Google Scholar 

  74. Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK (2009) ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res 104:531–540

    Article  PubMed  CAS  Google Scholar 

  75. Wei L, Roberts W, Wang L, Yamada M, Zhang S, Zhao Z, Rivkees SA, Schwartz RJ, Imanaka-Yoshida K (2001) Rho-kinases play an obligatory role in vertebrate embryonic organogenesis. Development 128:2953–2962

    PubMed  CAS  Google Scholar 

  76. Whitlock NA, Harrison B, Mixon T, Yu XQ, Wilson A, Gerhardt B, Eberhart DE, Abuin A, Rice DS (2009) Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J Ocul Pharmacol Ther 25:187–194

    Article  PubMed  CAS  Google Scholar 

  77. Wibberley A, Chen Z, Hu E, Hieble JP, Westfall TD (2003) Expression and functional role of rho-kinase in rat urinary bladder smooth muscle. Br J Pharmacol 138:757–766

    Article  PubMed  CAS  Google Scholar 

  78. Yoneda A, Multhaupt HA, Couchman JR (2005) The rho-kinases I and II regulate different aspects of myosin II activity. J Cell Biol 170:443–453

    Article  PubMed  CAS  Google Scholar 

  79. Yoneda A, Ushakov D, Multhaupt HA, Couchman JR (2007) Fibronectin matrix assembly requires distinct contributions from rho-kinases I and -II. Mol Biol Cell 18:66–75

    Article  PubMed  CAS  Google Scholar 

  80. Zhang J, Bian HJ, Li XX, Liu XB, Sun JP, Li N, Zhang Y, Ji XP (2010) ERK-MAPK signaling opposes rho-kinase to reduce cardiomyocyte apoptosis in heart ischemic preconditioning. Mol Med 16:307–315

    PubMed  CAS  Google Scholar 

  81. Zhang YM, Bo J, Taffet GE, Chang J, Shi J, Reddy AK, Michael LH, Schneider MD, Entman ML, Schwartz RJ, Wei L (2006) Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. Faseb J 20:916–925

    Article  PubMed  CAS  Google Scholar 

  82. Zhou Z, Meng Y, Asrar S, Todorovski Z, Jia Z (2009) A critical role of rho-kinase ROCK2 in the regulation of spine and synaptic function. Neuropharmacology 56:81–89

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Riley Children’s Foundation, the Indiana University Department of Pediatrics (Cardiology), and the National Institutes of Health (NIH P01 HL085098 to LW).

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  1. Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University, School of Medicine, 1044 West Walnut Street, Indianapolis, IN, 46202-5225, USA

    Jianjian Shi, Lumin Zhang & Lei Wei

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Correspondence to Lei Wei.

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Shi, J., Zhang, L. & Wei, L. Rho-Kinase in Development and Heart Failure: Insights From Genetic Models. Pediatr Cardiol 32, 297–304 (2011). https://doi.org/10.1007/s00246-011-9920-0

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