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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Review Article

An Update on the Association of Protein Kinases with Cardiovascular Diseases

Author(s): Fakhra Amin, Azaj Ahmed, Anna Feroz, Peerzada Shariq Shaheen Khaki, Mohd Shahnwaz Khan, Shams Tabrez*, Syed Kashif Zaidi, Wesam H. Abdulaal, Anas Shamsi, Wajihullah Khan and Bilqees Bano*

Volume 25 , Issue 2 , 2019

Page: [174 - 183] Pages: 10

DOI: 10.2174/1381612825666190312115140

Price: $65


Background: Protein kinases are the enzymes involved in phosphorylation of different proteins which leads to functional changes in those proteins. They belong to serine-threonine kinases family and are classified into the AGC (Protein kinase A/ Protein kinase G/ Protein kinase C) families of protein and Rho-associated kinase protein (ROCK). The AGC family of kinases are involved in G-protein stimuli, muscle contraction, platelet biology and lipid signaling. On the other hand, ROCK regulates actin cytoskeleton which is involved in the development of stress fibres. Inflammation is the main signal in all ROCK-mediated disease. It triggers the cascade of a reaction involving various proinflammatory cytokine molecules.

Methods: Two ROCK isoforms are found in mammals and invertebrates. The first isoforms are present mainly in the kidney, lung, spleen, liver, and testis. The second one is mainly distributed in the brain and heart.

Results: ROCK proteins are ubiquitously present in all tissues and are involved in many ailments that include hypertension, stroke, atherosclerosis, pulmonary hypertension, vasospasm, ischemia-reperfusion injury and heart failure. Several ROCK inhibitors have shown positive results in the treatment of various disease including cardiovascular diseases.

Conclusion: ROCK inhibitors, fasudil and Y27632, have been reported for significant efficiency in dropping vascular smooth muscle cell hyper-contraction, vascular inflammatory cell recruitment, cardiac remodelling and endothelial dysfunction which highlight ROCK role in cardiovascular diseases.

Keywords: Cardiovascular disease, Fasudil and Y27632, Protein kinase, ROCK, Rock isomers, Rock inhibitors, Rho-kinase.

Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298(5600): 1912-34.
Dhanasekaran N, Premkumar Reddy E. Signaling by dual specificity kinases. Oncogene 1998; 17: 1447-55.
Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy. Int J Mol Med 2017; 40(2): 271-80.
Krupa A, Abhinandan K, Srinivasan N. KinG: a database of protein kinases in genomes. Nucleic Acids Res 2004; 32: 153-5.
Indo HP, Hawkins CL, Naknishi I, et al. Role of mitochondrial reactive oxygen species in the activation of cellular signals, molecules and function. Handb Exp Pharmacol 2017; 240: 439-56.
Cohen P. Protein kinases-the major drug targets of the twenty-first century? Nat Rev Drug Discov 2002; 1: 309-15.
Han E, McGonigal T. Role of focal adhesion kinase in human cancer: a potential target for drug discovery. Anticancer Agents Med Chem 2007; 7: 681-4.
Hardie D. AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 2007; 47: 185-210.
Pardo-Pastor C, Rubio-Moscardo F, Vogel-González M, et al. Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses. Proc Natl Acad Sci 2018; 115(8): 1925-30.
Pearce LR, Komander D and, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010; 11(1): 9-22.
Kannan N, Haste N, Taylor SS and, Neuwald AF. The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module. Proc Natl Acad Sci USA 2007; 104(4): 1272-7.
Amin E, Dubey BN, Zhang SC, et al. Rho-kinase: regulation, (dys) function, and inhibition. Biological Chem 2013; 394(11): 1399-410.
Singh RM, Cummings E, Pantos C, Singh J. Protein kinase C and cardiac dysfunction: a review. Heart Fail Rev 2017; 22(6): 843-59.
Kumar R, Singh VP, Baker KM. Kinase inhibitors for cardiovascular disease. J Mol Cell Cardiol 2007; 42(1): 1-11.
Girouard MP, Pool M, Alchini R, Rambaldi I, Fournier AE, Rho A. Proteolysis Regulates the Actin Cytoskeleton in Response to Oxidative Stress. PLoS One 2016; 11(12): e0168641.
Johnson DS, Chen YH. Ras family of small GTPases in immunity and inflammation. Curr Opin Pharmacol 2012; 12(4): 458-63.
Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 2002; 16(13): 1587-609.
Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 2007; 129(5): 865-77.
Rai A, Goody RS, Müller MP. Multivalency in Rab effector interactions. Small GTPases 2017; 1-7.
Hahmann C, Schroeter T. Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity. Cell Mol Life Sci 2010; 67(2): 171-7.
Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviours. Nat Rev Mol Cell Biol 2003; 4(6): 446-56.
Leung T, Chen XQ, Manser E, Lim L. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 1996; 16(10): 5313-27.
Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol 2013; 62(4): 10.
Hernández-Cuevas NA, Jhingan GD, Petropolis D, Vargas M, Guillen N. Acetylation is the most abundant actin modification in Entamoeba histolytica and modifications of actin’s amino-terminal domain change cytoskeleton activities. Cell Microbiol 2018; e12983.
Tönges L, Frank T, Tatenhorst L, et al. Inhibition of Rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 2012; 11: 3355-70.
Dahal BK, Kosanovic D, Pamarthi PK, et al. Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension. Europ Respirat J 2010; 36(4): 808-18.
Samuel MS, Lopez JI, McGhee EJ, et al. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce interfollicular epidermal hyperplasia and tumor growth. Cancer Cell 2011; 19(6): 776-91.
Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation. Clin Exp Immunol 2007; 147(2): 227-35.
Abbas AB, Lichtman AH. Ch.2 Innate Immunity In: Saunders (Elsevier) Basic Immunology Functions and disorders of the immune system. 2009. 3rd ed.
Nozaki Y, Kinoshita K, Hino S, et al. Signaling Rho-kinase mediates inflammation and apoptosis in T cells and renal tubules in cisplatin nephrotoxicity. Am J Physiol Renal Physiol 2015; 308(8): F899-909.
Rikitake Y, Liao JK. Rho GTPases, Statins, and Nitric Oxide. Circ Res 2005; 97(12): 1232-5.
Shimokawa H, Seto M, Katsumata N, et al. Rho-kinase-mediated pathway induces enhanced myosin light-chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999; 43: 1029-39.
Kandabashi T, Shimokawa H, Miyata K, et al. Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β. Circulation 2000; 101: 1319-23.
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; 39: 245-50.
Ikegaki I, Hattori T, Yamaguchi T, et al. Involvement of Rho-kinase in vascular remodeling caused by long-term inhibition of nitric oxide synthesis in rats. Eur J Pharmacol 2001; 427: 69-75.
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; 24: 1842-7.
Bao W, Hu E, Tao L, et al. Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury. Cardiovasc Res 2004; 61(3): 548-58.
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; 292(6): 2598-606.
Zhang J, Li XX, Bian HJ, Liu XB, Ji XP, Zhang Y. Inhibition of the activity of Rho-kinase reduces cardiomyocyte apoptosis in heart ischemia/reperfusion via suppressing JNK-mediated AIF translocation. Clin Chim Acta 2009; 401(1-2): 76-80.
Shibata I, Yoshitomi O, Use T, et al. Administration of the Rho-kinase inhibitor fasudil before ischemia or just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium in swine. Cardiovasc Drugs Ther 2008; 22(4): 293-8.
Zhang J, Xu F, Liu XB, Bi SJ, Lu QH. Increased Rho kinase activity in patients with heart ischemia/reperfusion. Perfusion 2018.
Hausenloy DJ, Yellon DM. Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev 2007; 12(3-4): 217-34.
Cadete VJ, Sawicka J, Polewicz D, Doroszko A, Wozniak M, Sawicki G. Effect of the Rho kinase inhibitor Y-27632 on the proteome of hearts with ischemia-reperfusion injury. Proteomics 2010; 10(24): 4377-85.
Zhang J, Bian HJ, Li XX, et al. ERK-MAPK signaling opposes Rho-kinase to reduce cardiomyocyte apoptosis in heart ischemic preconditioning. Mol Med 2010; 16(7-8): 307-31.
Zhao JL, Yang YJ, Pei WD, Sun YH, You SJ, Gao RL. Remote periconditioning reduces myocardial no-reflow by the activation of K ATP channel via inhibition of Rho-kinase. Int J Cardiol 2009; 133(2): 179-84.
Sakamoto K, Nakahara T, Ishii K. Rho-Rho kinase pathway is involved in the protective effect of early ischemic preconditioning in the rat heart. Biol Pharm Bull 2011; 34(1): 156-9.
Demiryurek S, Kara AF, Celik A, Babul A, Tarakcioglu M, Demiryurek AT. Effects of fasudil, a Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats. Eur J Pharmacol 2005; 527(1-3): 129-40.
Dong LY, Qiu XX, Zhuang Y. Xeu S. Y-27632, a Rho-kinase inhibitor, attenuates myocardial ischemia-reperfusion injury in rats. Int J Mol Med 2019; 43(4): 1911-9.
Kobayashi M, Tanoue Y, Eto M, et al. A Rho-kinase inhibitor improves cardiac function after 24-hour heart preservation. J Thorac Cardiovasc Surg 2008; 136(6): 1586-92.
Haudek SB, Gupta D, Dewald O, et al. Rho kinase-1 mediates cardiac fibrosis by regulating fibroblast precursor cell differentiation. Cardiovasc Res 2009; 83(3): 511-8.
Yang W, Zhou G, Yu T, et al. Critical role of ROCK2 activity in facilitating mucosal CD4+ T cell activation in inflammatory bowel disease. J Autoimmun 2018; 89: 125-38.
Lackland DT, Weber MA. Global burden of cardiovascular disease and stroke: hypertension at the core. Canad J Cardiol 2015; 31(5): 569-71.
MendisShanthi, PuskaPekka, Norrving Bo. Global atlas on cardiovascular disease prevention and control .Geneva: World Health Organization in collaboration with the World Heart Federation and the World Stroke Organization. 2011. 1st ed p. 38.ISBN 9789241564373.
Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens 1999; 12(12 Pt 3): 205S-13S.
Schulz E, Gori T, Munzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 2011; 34(6): 665-73.
Ocaranza MP, Rivera P, Novoa U, et al. Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension. J Hypertens 2011; 29: 706-15.
Tsounapi P, Saito M, Kitatani K, et al. Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats. Eur J Pharmacol 2012; 691: 182-9.
Hassona MD, Abouelnaga ZA, Elnakish MT, et al. Vascular hypertrophy-associated hypertension of profilin1 transgenic mouse model leads to functional remodeling of peripheral arteries. Am J Physiol Heart Circ Physiol 2010; 298(6): H2112-20.
Ruiz-Ortega M, Lorenzo O, Ruperez M, et al. Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension 2001; 38: 1382-7.
Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 2000; 52(4): 639-72.
de Cavanagh EM, Ferder M, Inserra F, Ferder L. Angiotensin II, mitochondria, cytoskeletal, and extracellular matrix connections: an integrating viewpoint. Am J Physiol Heart Circ Physiol 2009; 296(3): H550-8.
Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000; 86(5): 494-501.
Mukai Y, Shimokawa H, Matoba T, et al. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J 2001; 15(6): 1062-4.
Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol 2011; 301(2): H287-96.
Sun Q, Yue P, Ying Z, et al. Air pollution exposure potentiates hypertension through reactive oxygen species-mediated activation of Rho/ROCK. Arterioscler Thromb Vasc Biol 2008; 28(10): 1760-6.
Guilluy C, Bregeon J, Toumaniantz G, et al. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med 2010; 16(2): 183-90.
Wirth A, Benyo Z, Lukasova M, et al. G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med 2008; 14(1): 64-8.
Moriki N, Ito M, Seko T, et al. RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27(4): 263-70.
Tsounapi P, Saito M, Kitatani K, et al. Fasudil improves the endothelial dysfunction in the aorta of spontaneously hypertensive rats. Eur J Pharmacol 2012; 691: 182-9.
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(6): 1307-10.
Seko T, Ito M, Kureishi Y, et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res 2003; 92: 411-8.
Hassona MD, Abouelnaga ZA, Elnakish MT, et al. Vascular hypertrophy-associated hypertension of profilin1 transgenic mouse model leads to functional remodeling of peripheral arteries. Am J Physiol Heart Cir Physiol 2010; 298: H2112-20.
Chan CK, Mak JC, Man RY, Vanhoutte PM. Rho kinase inhibitors prevent endothelium-dependent contractions in the rat aorta. J Pharmacol Exp Ther 2009; 329: 820-6.
Takeda K, Ichiki T, Tokunou T, et al. 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: 868-73.
Rikitake Y, Liao JK. Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells. Circulation 2005; 111: 3261-8.
Ito K, Hirooka Y, Sakai K, et al. 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(12): 1337-43.
Ito K, Hirooka Y, Kishi T, et al. Rho/Rho-kinase pathway in the brainstem contributes to hypertension caused by chronic nitric oxide synthase inhibition. Hypertension 2004; 43(2): 156-62.
Ito K, Kimura Y, Hirooka Y, Sagara Y, Sunagawa K. Activation of Rho-kinase in the brainstem enhances sympathetic drive in mice with heart failure. Auton Neurosci 2008; 142(1-2): 77-81.
Surma M, Wei L, Shi J. Rho kinase as a therapeutic target in cardiovascular disease. Future Cardiol 2011; 7(5): 657-71.
Zhou Q, Liao JK. Rho kinase: an important mediator of atherosclerosis and vascular disease. Curr Pharm Des 2009; 15(27): 3108-15.
Hiroi Y, Noma K, Kim HH, et al. Neuroprotection mediated by upregulation of endothelial nitric oxide synthase in Rho-associated, coiled-coil-containing kinase 2 deficient mice. Circ Res 2018; 82(4): 1195-204.
Rabinovitch M. Pulmonary hypertension: updating a mysterious disease. Cardiovasc Res 1997; 34: 268-72.
Rubin LJ. Cellular and molecular mechanisms responsible for the pathogenesis of primary pulmonary hypertension. Pediatr Pulmonol Suppl 1999; 18: 194-7.
Kimura H, Kasahara Y, Kurosu K, et al. Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Lab Invest 1998; 78: 571-81.
Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003; 361: 1533-44.
Mill C, George SJ. Wnt signalling in smooth muscle cells and its role in cardiovascular disorders. Cardiovasc Res 2012; 95(2): 233-40.
Guilluy C, Rolli-Derkinderen M, Tharaux PL, Melino G, Pacaud P, Loirand G. Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 2007; 282: 2918-28.
Guilluy C, Eddahibi S, Agard C, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med 2009; 179: 1151-8.
Garcia JH, Yoshida Y, Chen H, et al. Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol 1993; 142: 623-35.
Shin HK, Salomone S, Potts EM, et al. Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms. J Cereb Blood Flow Metab 2007; 27: 998-1009.
Ding J, Li QY, Wang X, Sun CH, Lu CZ, Xiao BG. Fasudil protects hippocampal neurons against hypoxia-reoxygenation injury by suppressing microglial inflammatory responses in mice. J Neurochem 2010; 114: 1619-29.
Feske SK, Sorond FA, Henderson GV, et al. Increased leukocyte ROCK activity in patients after acute ischemic stroke. Brain Res 2009; 1257: 89-93.
Kahles T, Luedike P, Endres M, et al. NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke 2007; 38(11): 3000-6.
Wu J, Li J, Hu H, Liu P, Fang Y, Wu D. Rho-kinase inhibitor, fasudil, prevents neuronal apoptosis via the Akt activation and PTEN inactivation in the ischemic penumbra of rat brain. Cell Mol Neurobiol 2012; 32: 1187-97.
Satoh S, Utsunomiya T, Tsurui K, et al. Pharmacological profile of hydroxy fasudil as a selective rho kinase inhibitor on ischemic brain damage. Life Sci 2001; 69(12): 1441-53.
Vesterinen HM, Currie GL, Carter S, et al. Systematic review and stratified meta-analysis of the efficacy of RhoA and Rho kinase inhibitors in animal models of ischaemic stroke. Syst Rev 2013; 2: 33.
Definition of Heart failure. Medical Dictionary. MedicineNet 2011.
Chronic Heart Failure: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care: Partial Update. National Clinical Guideline Centre 2010; pp. 19-24.
McDonagh Theresa A Oxford textbook of heart failure. Oxford: Oxford University Press 2011; p. 3. ISBN 9780199577729.
O'Connor, Christopher M Managing Acute Decompensated Heart Failure a Clinician’s Guide to Diagnosis and Treatment. London: Informal Healthcare 2005; p. 572. ISBN 9780203421345.
McMurray JJ, Pfeffer MA. Heart failure 2005; 365(9474): 1877-89.
Chronic Heart Failure National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care: Partial Update. National Clinical Guideline Centre 2010; pp. 38-70.
Willard & Spackman’s occupational therapy. 12th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins 2014; p. 1124. ISBN 9781451110807.
Bootman MD. Calcium signaling. Cold Spring Harb Perspect Biol 2012; 4(7): a011171.
Lincoln TM. Myosin phosphatase regulatory pathways: Different functions or redundant functions? Circ Res 2007; 100: 10-2.
Feng J, Ito M, Ichikawa K, et al. Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase. J Biol Chem 1999; 274: 37385-90.
Kiss E, Muranyi A, Csortos C, et al. Integrin-linked kinase phosphorylates the myosin phosphatase target subunit at the inhibitory site in platelet cytoskeleton. Biochem J 2002; 365: 79-87.
Manintveld OC, Verdouw PD, Duncker DJ. The RISK of ROCK. Am J Physiol Heart Circ Physiol 2007; 292: H2563-5.
Kobayashi N, Takeshima H, Fukushima H, et al. Cardioprotective effects of pitavastatin on cardiac performance and remodeling in failing rat hearts. Am J Hypertens 2009; 22: 176-82.
Dulak J, Jozkowicz A. Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy. Curr Cancer Drug Targets 2005; 5: 579-94.
Fritz G, Kaina B. Rho GTPases: promising cellular targets for novel anticancer drugs. Curr Cancer Drug Targets 2006; 6: 1-14.
Kuo IY, Ehrlich BE. Signaling in muscle contraction. Cold Spring Harb Perspect Biol 2015; 7(2): a006023.
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; 22(2): 1056-69.
Sasaki Y, Suzuki M, Hidaka H. The novel and specific Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine as a probing molecule for Rho-kinase-involved pathway. Pharmacol Ther 2002; 93: 225-32.
Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E. Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial. J Neurol Sci 2005; 238: 31-9.
Zhao J, Zhou D, Guo J, et al. Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo) 2006; 46: 421-8.
Suzuki Y, Shibuya M, Satoh S, Sugimoto Y, Takakura K. A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg Neurol 2007; 68: 126-31.
Laufs U, Endres M, Stagliano N, et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest 2000; 106: 15-24.
Toshima Y, Satoh S, Ikegaki I, et al. A new model of cerebral microthrombosis in rats and the neuroprotective effect of a Rho-kinase inhibitor. Stroke 2000; 31: 2245-50.
Rikitake Y, Kim HH, Huang Z, et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke 2005; 36: 2251-7.
Satoh S, Toshima Y, Ikegaki I, Iwasaki M, Asano T. Wide therapeutic time window for fasudil neuroprotection against ischemia-induced delayed neuronal death in gerbils. Brain Res 2007; 1128: 175-80.
Shimokawa H, Hiramori K, Iinuma H, et al. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol 2002; 40: 751-61.
Vicari RM, Chaitman B, Keefe D, et al. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J Am Coll Cardiol 2005; 46: 1803-11.
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; 91: 391-2.
Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by a Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002; 105: 1545-7.
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; 111: 2741-7.
Narumiya S, Ishizaki T, Uehata M. Use and properties of ROCK-specific inhibitor Y-27632. Methods Enzymol 2000; 325: 273-84.
Olson MF. Applications for ROCK kinase inhibition. Curr Opin Cell Biol 2008; 20(2): 242-8.
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.
Bain J, Plater L, Elliott M, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J 2007; 408(3): 297-15.
Liao JK, Seto M, Noma K. Rho kinase (ROCK) inhibitors. J Cardiovasc Pharmacol 2007; 50(1): 17-24.
Lohn M, Plettenburg O, Ivashchenko Y, et al. Pharmacological characterization of SAR407899, a novel Rho-kinase inhibitor. Hypertension 2009; 54(3): 676-83.
Kast R, Schirok H, Figueroa-Perez S, et al. Cardiovascular effects of a novel potent and highlyselectiveazaindole-based inhibitor of Rho-kinase. Br J Pharmacol 2007; 152(7): 1070-80.
Doe C, Bentley R, Behm DJ, et al. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther 2007; 320(1): 89-98.
Dhaliwal JS. BadejoAMJr, Casey DB, Murthy SN, Kadowitz PJ. Analysis of pulmonary vasodilator responses to SB-772077-B [4-(7-((3-amino-1-pyrrolidinyl) carbonyl)-1-ethyl-1Himidazo(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(1): 334-41.
Boerma M, Fu Q, Wang J, et al. 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(7): 709-18.
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; 22: 8467-77.
Moncada S. A2. Nitric oxide and bioenergetics: Physiology and pathophysiology. Nitric Oxide 2007; 17: 9.
Jakala P, Pere E, Lehtinen R, Turpeinen A, Korpela R, Vapaatalo H. Cardiovascular activity of milk casein-derived tripeptides and plant sterols in spontaneously hypertensive rats. J Physiol Pharmacol 2009; 60: 11-20.
Shibuya M, Suzuki Y, Sugita K, et al. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J Neurosurg 1992; 76: 571-7.
Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductaseinhibitors. Circulation 1998; 97: 1129-35.
Takemoto M, Sun J, Hiroki J, et al. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 2002; 106: 57-62.
Eto M, Barandier C, Rathgeb L, et al. Thrombin suppresses endothelial nitric oxide synthase and upregulatesendothelin-converting enzyme-1 expression by distinct pathways: role of Rho/ROCK and mitogen-activated protein kinase. Circ Res 2001; 89(7): 583-90.

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