470
Views
23
CrossRef citations to date
0
Altmetric
Review

Targeting Rho-associated coiled-coil forming protein kinase (ROCK) in cardiovascular fibrosis and stiffening

, , &
Pages 47-62 | Received 11 Aug 2019, Accepted 04 Jan 2020, Published online: 09 Jan 2020

References

  • Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014 Feb;71(4):549–574.
  • Leung T, Chen XQ, Manser E, et al. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol. 1996 Oct;16(10):5313–5327.
  • Kimura K, Ito M, Amano M, et al. Regulation of myosin phosphatase by Rho and Rho-associated Kinase (Rho-Kinase). Science. 1996;273(5272):245.
  • Zhou Q, Gensch C, Liao JK. Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease. Trends Pharmacol Sci. 2011 Mar;32(3):167–173.
  • Cook C, Cole G, Asaria P, et al. The annual global economic burden of heart failure. Int J Cardiol. 2014 Feb 15;171(3):368–376.
  • Lowery DM, Clauser KR, Hjerrild M, et al. Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. Embo J. 2007 May 2;26(9):2262–2273.
  • Riento K, Guasch RM, Garg R, et al. RhoE binds to ROCK I and inhibits downstream signaling. Mol Cell Biol. 2003 Jun;23(12):4219–4229.
  • Ward Y, Yap SF, Ravichandran V, et al. The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J Cell Biol. 2002 Apr 15;157(2):291–302.
  • Ferretti R, Palumbo V, Di Savino A, et al. Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis. Dev Cell. 2010 Mar 16;18(3):486–495.
  • Knipe RS, Tager AM, Liao JK. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67(1):103.
  • Arber S, Barbayannis FA, Hanser H, et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature. 1998 June 01;393(6687):805–809.
  • Croft DR, Olson MF. The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Mol Cell Biol. 2006 Jun;26(12):4612–4627.
  • Shi J, Wei L. Rho kinase in the regulation of cell death and survival. Arch Immunol Ther Exp (Warsz). 2007 Mar-Apr;55(2):61–75.
  • Sladojevic N, Yu B, Liao JK. ROCK as a therapeutic target for ischemic stroke. Expert Rev Neurother. 2017 Dec;17(12):1167–1177.
  • Rikitake Y, Oyama N, Wang CY, et al. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1± haploinsufficient mice. Circulation. 2005 Nov 8;112(19):2959–2965.
  • Zhang YM, Bo J, Taffet GE, et al. Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosis. Faseb J. 2006 May;20(7):916–925.
  • Shi J, Zhang YW, Summers LJ, et al. Disruption of ROCK1 gene attenuates cardiac dilation and improves contractile function in pathological cardiac hypertrophy. J Mol Cell Cardiol. 2008 Mar;44(3):551–560.
  • Shi J, Surma M, Yang Y, et al. Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging. Faseb J. 2019 Jun;33(6):7348–7362.
  • Sunamura S, Satoh K, Kurosawa R, et al. Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice. Proc Natl Acad Sci U S A. 2018;115(30):E7129.
  • Shimizu T, Narang N, Chen P, et al. Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction. JCI Insight. 2017 Jul 6;2:13.
  • Yue X, Yang X, Lin X, et al. Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure. Cell Death Dis. 2014 Jun 5;5:e1284.
  • Zhang J, Chang L, Chen C, et al. Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor. Cardiovasc Res. 2011 Jul 1;91(1):90–98.
  • Olson EN, Nordheim A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol. 2010 May;11(5):353–365.
  • Esnault C, Stewart A, Gualdrini F, et al. Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes Dev. 2014 May 1;28(9):943–958.
  • Yu-Wai-Man C, Spencer-Dene B, Lee RMH, et al. Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. Sci Rep. 2017 March 31;7(1):518.
  • Ohashi K, Nagata K, Maekawa M, et al. Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem. 2000 Feb 4;275(5):3577–3582.
  • Hill CS, Wynne J, Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell. 1995 Jun 30; 81(7):1159–1170.
  • Sakai N, Chun J, Duffield JS, et al. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. Faseb J. 2013 May;27(5):1830–1846.
  • Davis J, Burr AR, Davis GF, et al. A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell. 2012 Oct 16;23(4):705–715.
  • EM S, JE T, LB S, et al. Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ Res. 2010 Jul 23;107(2):294–304.
  • Akhmetshina A, Dees C, Pileckyte M, et al. Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. Arthritis Rheum. 2008 Aug;58(8):2553–2564.
  • Yu OM, Miyamoto S, Brown JH. Myocardin-related transcription factor A and yes-associated protein exert dual control in G protein-coupled receptor- and RhoA-mediated transcriptional regulation and cell proliferation. Mol Cell Biol. 2016 Jan 1; 36(1):39–49.
  • Kranenburg O, Poland M, van Horck FPG, et al. Activation of RhoA by lysophosphatidic acid and Gα12/13 Subunits in neuronal cells: induction of neurite retraction. Mol Cell Biol. 1999 June 1;10(6):1851–1857.
  • Siehler S. Regulation of RhoGEF proteins by G12/13-coupled receptors. Br J Pharmacol. 2009 Sep;158(1):41–49.
  • Singh I, Knezevic N, Ahmmed GU, et al. Galphaq-TRPC6-mediated Ca2+ entry induces RhoA activation and resultant endothelial cell shape change in response to thrombin. J Biol Chem. 2007 Mar 16;282(11):7833–7843.
  • Huang X, Yang N, Fiore VF, et al. Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol. 2012 Sep;47(3):340–348.
  • Hansen CG, Moroishi T, Guan KL. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 2015 Sep;25(9):499–513.
  • Szeto SG, Narimatsu M, Lu M, et al. YAP/TAZ are mechanoregulators of TGF-β-Smad signaling and renal fibrogenesis. J Am Soc Nephrol. 2016;27(10):3117.
  • Zhao B, Ye X, Yu J, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008 Jul 15;22(14):1962–1971.
  • Thomasy SM, Morgan JT, Wood JA, et al. Substratum stiffness and latrunculin B modulate the gene expression of the mechanotransducers YAP and TAZ in human trabecular meshwork cells. Exp Eye Res. 2013;113:66–73.
  • Wada K-I, Itoga K, Okano T, et al. Hippo pathway regulation by cell morphology and stress fibers. Development. 2011;138(18):3907.
  • Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011 Jun 8;474(7350):179–183.
  • Aragona M, Panciera T, Manfrin A, et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 2013 Aug 29;154(5):1047–1059.
  • Milenkovic U, Ilg MM, Zuccato C, et al. Simvastatin and the Rho-kinase inhibitor Y-27632 prevent myofibroblast transformation in Peyronie’s disease-derived fibroblasts via inhibition of YAP/TAZ nuclear translocation. BJU Int. 2019 Apr;123(4):703–715.
  • Yu FX, Zhao B, Panupinthu N, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012 Aug 17;150(4):780–791.
  • Ibar C, Kirichenko E, Keepers B, et al. Tension-dependent regulation of mammalian Hippo signaling through LIMD1. J Cell Sci. 2018 Mar 2;131:5.
  • Liu G, Ma C, Yang H, et al. Transforming growth factor β and its role in heart disease. Exp Ther Med. 2017 May;13(5):2123–2128.
  • Roberts AB, Sporn MB, Assoian RK, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171.
  • Yamanaka M, Shegogue D, Pei H, et al. Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation. J Biol Chem. 2004 Dec 24;279(52):53994–54001.
  • Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993 Jul;122(1):103–111.
  • Datta PK, Blake MC, Moses HL. Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. J Biol Chem. 2000 Dec 22;275(51):40014–40019.
  • Kamaraju AK, Roberts AB. Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem. 2005 Jan 14; 280(2):1024–1036.
  • Chen S, Crawford M, RM D, et al. RhoA modulates Smad signaling during transforming growth factor-beta-induced smooth muscle differentiation. J Biol Chem. 2006 Jan 20;281(3):1765–1770.
  • Xu T, Wu M, Feng J, et al. RhoA/Rho kinase signaling regulates transforming growth factor-beta1-induced chondrogenesis and actin organization of synovium-derived mesenchymal stem cells through interaction with the Smad pathway. Int J Mol Med. 2012 Nov;30(5):1119–1125.
  • Itoh Y, Kimoto K, Imaizumi M, et al. Inhibition of RhoA/Rho-kinase pathway suppresses the expression of type I collagen induced by TGF-beta2 in human retinal pigment epithelial cells. Exp Eye Res. 2007 Mar;84(3):464–472.
  • Ji H, Tang H, Lin H, et al. Rho/Rock cross-talks with transforming growth factor-β/Smad pathway participates in lung fibroblast-myofibroblast differentiation. Biomed Rep. 2014 Nov;2(6):787–792.
  • Sandbo N, Lau A, Kach J, et al. Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-beta. Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L656–L66.
  • Jenkins RG, Su X, Su G, et al. Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. J Clin Invest. 2006 Jun;116(6):1606–1614.
  • Zhu M, Liu PY, Kasahara DI, et al. Role of Rho kinase isoforms in murine allergic airway responses. Eur Respir J. 2011;38(4):841.
  • Tharaux P-L, Bukoski RC, Rocha PN, et al. Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells. Eur Respir J. 2003;171(1):96.
  • Hasan Z, Palani K, Zhang S, et al. Rho kinase regulates induction of T-cell immune dysfunction in abdominal sepsis. Infect Immun. 2013 Jul;81(7):2499–2506.
  • Kobayashi M, Azuma E, Ido M, et al. A pivotal role of Rho GTPase in the regulation of morphology and function of dendritic cells. J Immunol. 2001 Oct 1;167(7):3585–3591.
  • Biswas PS, Gupta S, Chang E, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010 September 01;120(9):3280–3295.
  • Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A. 2014;111(47):16814.
  • Bansal SS, Ismahil MA, Goel M, et al. Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure. Circ Heart Fail. 2017 Mar;10(3):e003688.
  • Liu Y, Zhu H, Su Z, et al. IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCbeta/Erk1/2/NF-kappaB-dependent signaling pathway. Int Immunol. 2012 Oct;24(10):605–612.
  • Peng H, Sarwar Z, Yang XP, et al. Profibrotic role for interleukin-4 in cardiac remodeling and dysfunction. Hypertension. 2015 Sep;66(3):582–589.
  • Huang H, Kong D, Byun KH, et al. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat Neurosci. 2012 Oct;15(10):1391–1398.
  • Bellien J, Favre J, Iacob M, et al. Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. Hypertension. 2010;55(3):674–680.
  • Kataoka C, Egashira K, Inoue S, et al. Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension. 2002 Feb;39(2):245–250.
  • Kazakov A, Hall R, Jagoda P, et al. Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis. Cardiovasc Res. 2013 Nov 1;100(2):211–221.
  • Kim NN, Villegas S, Summerour SR, et al. Regulation of cardiac fibroblast extracellular matrix production by bradykinin and nitric oxide. J Mol Cell Cardiol. 1999 Feb;31(2):457–466.
  • Takemoto M, Sun J, Hiroki J, et al. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation. 2002 Jul 2;106(1):57–62.
  • Eto M, Barandier C, Rathgeb L, et al. 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 Sep 28;89(7):583–590.
  • Ming XF, Viswambharan H, Barandier C, et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol. 2002 Dec;22(24):8467–8477.
  • Rikitake Y, Kim HH, Huang Z, et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke. 2005 Oct;36(10):2251–2257.
  • Wolfrum S, Dendorfer A, Rikitake Y, et al. Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol. 2004 Oct;24(10):1842–1847.
  • Vemula S, Shi J, Hanneman P, et al. ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Blood. 2010 Mar 4;115(9):1785–1796.
  • Kovacic JC, Mercader N, Torres M, et al. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition. Circulation. 2012;125(14):1795–1808.
  • Krizbai IA, Gasparics Á, Nagyőszi P, et al. Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation. Plos One. 2015;10(3):e0119655.
  • Peng H, Li Y, Wang C, et al. ROCK1 induces endothelial-to-mesenchymal transition in glomeruli to aggravate albuminuria in diabetic nephropathy. Sci Rep. 2016 Feb 04;6:20304. online.
  • Wu Q, Ouyang C, Xie L, et al. The ROCK inhibitor, thiazovivin, inhibits human corneal endothelialtomesenchymal transition/epithelialtomesenchymal transition and increases ionic transporter expression. Int J Mol Med. 2017 Oct;40(4):1009–1018.
  • Shields MA, Krantz SB, Bentrem DJ, et al. Interplay between beta1-integrin and Rho signaling regulates differential scattering and motility of pancreatic cancer cells by snail and Slug proteins. J Biol Chem. 2012 Feb 24;287(9):6218–6229.
  • Kovacic JC, Dimmeler S, Harvey RP, et al. Endothelial to mesenchymal transition in cardiovascular disease. J Am Coll Cardiol. 2019;73(2):190.
  • Humphrey JD, Dufresne ER, Schwartz MA. Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol. 2014 Dec;15(12):802–812.
  • Lacolley P, Regnault V, Segers P, et al. Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and disease. Physiol Rev. 2017;97(4):1555–1617.
  • Margadant F, Chew LL, Hu X, et al. Mechanotransduction in vivo by repeated talin stretch-relaxation events depends upon vinculin. PLoS Biol. 2011;9(12):e1001223.
  • Joshi B, Strugnell SS, Goetz JG, et al. Phosphorylated Caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion. Cancer Res. 2008;68(20):8210.
  • Davies LM, Purves GI, Barrett-Jolley R, et al. Interaction with caveolin-1 modulates vascular ATP-sensitive potassium (KATP) channel activity. J Physiol. 2010 Sep 1;588(Pt 17):3255–3266.
  • Rashid-Doubell F, Tannetta D, Redman CW, et al. Caveolin-1 and lipid rafts in confluent BeWo trophoblasts: evidence for Rock-1 association with caveolin-1. Placenta. 2007 Feb-Mar;28(2–3):139–151.
  • Gingras D, Gauthier F, Lamy S, et al. Localization of RhoA GTPase to endothelial caveolae-enriched membrane domains. Biochem Biophys Res Commun. 1998 Jun 29;247(3):888–893.
  • Halayko AJ, Tran T, Gosens R. Phenotype and functional plasticity of airway smooth muscle. Proc Am Thorac Soc. 2008 Jan 01;5(1):80–88.
  • Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016 Mar 15;44(3):450–462.
  • Zandi S, Nakao S, Chun KH, et al. ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. Cell Rep. 2015 Feb 24;10(7):1173–1186.
  • Liu C, Li Y, Yu J, et al. Targeting the Shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil. Plos One. 2013;8(2):e54841.
  • Lee TM, Lin SZ, Chang NC. Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho-kinase signalling in infarcted rats. J Cell Mol Med. 2018 Feb;22(2):1056–1069.
  • Sanz-Moreno V, Gaggioli C, Yeo M, et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell. 2011 Aug 16;20(2):229–245.
  • Tugal D, Liao X, Jain MK. Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1135–1144.
  • Kaess BM, Rong J, Larson MG, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012 Sep 5;308(9):875–881.
  • Weisbrod RM, Shiang T, Al Sayah L, et al. Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension. 2013 Dec;62(6):1105–1110.
  • Noma K, Goto C, Nishioka K, et al. Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness. J Am Coll Cardiol. 2007 Feb 13;49(6):698–705.
  • Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997 Oct 30;389(6654):990–994.
  • Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005 Mar;91(3):391–392.
  • González A, Schelbert EB, Díez J, et al. Myocardial interstitial fibrosis in heart failure. J Am Coll Cardiol. 2018;71(15):1696.
  • Okamoto R, Li Y, Noma K, et al. FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2. Faseb J. 2013 Apr;27(4):1439–1449.
  • McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993–1004.
  • Burke RM, Lighthouse JK, Mickelsen DM, et al. Sacubitril/valsartan decreases cardiac fibrosis in left ventricle pressure overload by restoring PKG signaling in cardiac fibroblasts. Circ Heart Fail. 2019 Apr;12(4):e005565.
  • de Jong S, van Veen TA, van Rijen HV, et al. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol. 2011 Jun;57(6):630–638.
  • O’Hanlon R, Grasso A, Roughton M, et al. Prognostic significance of myocardial fibrosis in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2010 Sep 7;56(11):867–874.
  • Dzeshka MS, Lip GYH, Snezhitskiy V, et al. Cardiac Fibrosis in Patients With Atrial Fibrillation. J Am Coll Cardiol. 2015;66(8):943.
  • Ellawindy A, Satoh K, Sunamura S, et al. Rho-kinase inhibition during early cardiac development causes arrhythmogenic right ventricular cardiomyopathy in mice. Arterioscler Thromb Vasc Biol. 2015 Oct;35(10):2172–2184.
  • Liu L-J, Yao F-J, Lu G-H, et al. The role of the Rho/ROCK pathway in Ang II and TGF-β1-induced atrial remodeling. Plos One. 2016;11(9):e0161625.
  • Travers Joshua G, Kamal Fadia A, Robbins J, et al. Cardiac Fibrosis. Circ Res. 2016 March 18;118(6):1021–1040.
  • van den Borne SWM, Diez J, Blankesteijn WM, et al. Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol. 2009 Dec 01;7:30.
  • Hamid SA, Bower HS, Baxter GF. Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium. Am J Physiol Heart Circ Physiol. 2007 June 01;292(6):H2598–H606.
  • Lee TM, Lin SZ, Chang NC. Membrane ERalpha attenuates myocardial fibrosis via RhoA/ROCK-mediated actin remodeling in ovariectomized female infarcted rats. J Mol Med (Berl). 2014 Jan;92(1):43–51.
  • Preiss D, Campbell RT, Murray HM, et al. The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials. Eur Heart J. 2015 Jun 21;36(24):1536–1546.
  • Masumoto A, Mohri M, Shimokawa H, et al. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002 Apr 2;105(13):1545–1547.
  • Nohria A, Grunert ME, Rikitake Y, et al. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ Res. 2006 Dec 8;99(12):1426–1432.
  • Zhang X, Zhang X, Wang S, et al. Effects of fasudil on patients with pulmonary hypertension associated with left ventricular heart failure with preserved ejection fraction: a prospective intervention study. Can Respir J. 2018;2018:3148259.
  • Kang S, Tanaka T, Narazaki M, et al. Targeting Interleukin-6 Signaling in Clinic. Immunity. 2019 Apr 16;50(4):1007–1023.
  • Liao JK, Seto M, Noma K. Rho kinase (ROCK) inhibitors. J Cardiovasc Pharmacol. 2007 Jul;50(1):17–24.
  • Feng Y, LoGrasso PV, Defert O, et al. Rho Kinase (ROCK) inhibitors and their therapeutic potential. J Med Chem. 2016 Mar 24;59(6):2269–2300.
  • Shibuya M, Hirai S, Seto M, et al. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci. 2005 Nov 15;238(1–2):31–39.
  • Suzuki Y, Shibuya M, Satoh S, et al. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo). 2008 Jun;48(6):241–247. discussion 47-8.
  • Masumoto A, Hirooka Y, Shimokawa H, et al. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension. 2001 Dec 1;38(6):1307–1310.
  • Kishi T, Hirooka Y, Masumoto A, et al. Rho-kinase inhibitor improves increased vascular resistance and impaired vasodilation of the forearm in patients with heart failure. Circulation. 2005 May 31;111(21):2741–2747.
  • Jiang R, Ai Z-S, Jiang X, et al. Intravenous fasudil improves in-hospital mortality of patients with right heart failure in severe pulmonary hypertension. Hypertens Res. 2015 Aug 01;38(8):539–544.
  • Gabrielli L, Winter JL, Godoy I, et al. Increased rho-kinase activity in hypertensive patients with left ventricular hypertrophy. Am J Hypertens. 2014 Jun;27(6):838–845.
  • Dong M, Liao JK, Fang F, et al. Increased Rho kinase activity in congestive heart failure. Eur J Heart Fail. 2012 Sep;14(9):965–973.
  • Do EZ, Fukumoto Y, Sugimura K, et al. Rho-kinase activation in patients with heart failure. Circ J. 2013;77(10):2542–2550.
  • Ocaranza MP, Fierro C, Jalil JE, et al. Rho kinase activation in circulating leukocytes is related to hypertensive myocardial remodeling. Clin Sci (Lond). 2018 Aug 31;132(16):1837–1853.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.