Rho-kinase: important new therapeutic target in cardiovascular diseases.

Rho-kinase (ROCKs) belongs to the family of serine/threonine kinases and is an important downstream effector of the small GTP-binding protein RhoA. There are two isoforms of Rho-kinase, ROCK1 and ROCK2, and they have different functions with ROCK1 for circulating inflammatory cells and ROCK2 for vascular smooth muscle cells. It has been demonstrated that the RhoA/Rho-kinase pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, leading to the development of cardiovascular disease. The important role of Rho-kinase in vivo has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia-reperfusion injury, hypertension, pulmonary hypertension, stroke, and heart failure. Furthermore, the beneficial effects of fasudil, a selective Rho-kinase inhibitor, have been demonstrated for the treatment of several cardiovascular diseases in humans. Thus the Rho-kinase pathway is an important new therapeutic target in cardiovascular medicine.

[1]  M. Halks-Miller,et al.  Fasudil, a Rho-Kinase Inhibitor, Attenuates Angiotensin II–Induced Abdominal Aortic Aneurysm in Apolipoprotein E–Deficient Mice by Inhibiting Apoptosis and Proteolysis , 2005, Circulation.

[2]  Y. Kagaya,et al.  Long-term Inhibition of Rho-kinase Ameliorates Diastolic Heart Failure in Hypertensive Rats , 2008, Journal of cardiovascular pharmacology.

[3]  R. Alexander,et al.  Vasoconstriction: a new activity for platelet-derived growth factor. , 1986, Science.

[4]  Anne J. Ridley,et al.  ROCKs: multifunctional kinases in cell behaviour , 2003, Nature Reviews Molecular Cell Biology.

[5]  A. Takeshita,et al.  Rho-kinase is an important therapeutic target in cardiovascular medicine. , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[6]  Hiroko Oshima,et al.  ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles , 2005, The Journal of cell biology.

[7]  J. Sadoshima,et al.  Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro , 1993, Cell.

[8]  J. Brown,et al.  Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration. , 1999, Circulation research.

[9]  S. Gygi,et al.  Purification and Identification of Secreted Oxidative Stress-induced Factors from Vascular Smooth Muscle Cells* , 2000, The Journal of Biological Chemistry.

[10]  忠 神田橋 Inhibition of Myosin Phosphatase by Upregulated Rho-Kinase Plays a Key Role for Coronary Artery Spasm in a Porcine Model With Interleukin-1β , 2001 .

[11]  B. Olofsson,et al.  Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. , 1999, Cellular signalling.

[12]  B. Berk,et al.  Oxidative stress and vascular smooth muscle cell growth: a mechanistic linkage by cyclophilin A. , 2010, Antioxidants & redox signaling.

[13]  HiroakiShimokawa,et al.  Remnant Lipoproteins from Patients with Sudden Cardiac Death Enhance Coronary Vasospastic Activity Through Upregulation of Rho-Kinase , 2004 .

[14]  Peter Libby,et al.  Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. , 2007, The Journal of clinical investigation.

[15]  A. Takeshita,et al.  Rho/Rho-Kinase Pathway in the Brainstem Contributes to Hypertension Caused by Chronic Nitric Oxide Synthase Inhibition , 2004, Hypertension.

[16]  Tetsuya Matoba,et al.  Cyclophilin A enhances vascular oxidative stress and development of angiotensin II-induced aortic aneurysms , 2009, Nature Medicine.

[17]  R. Torres,et al.  The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure , 2010, Nature Medicine.

[18]  A. Takeshita,et al.  Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs. , 2000, American journal of physiology. Heart and circulatory physiology.

[19]  A. Takeshita,et al.  Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension , 2005, Heart.

[20]  D. Barford,et al.  Mechanism of multi-site phosphorylation from a ROCK-I:RhoE complex structure , 2008, The EMBO journal.

[21]  Hiroaki Shimokawa,et al.  Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. , 2003, Journal of the American College of Cardiology.

[22]  E. Krieger,et al.  State-of-the-Art lecture: influence of exercise training on neurogenic control of blood pressure in spontaneously hypertensive rats. , 1999, Hypertension.

[23]  Yutaka Kagaya,et al.  Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice , 2006, Circulation.

[24]  樋詰 貴登士,et al.  Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo : a possible link between stress and coronary vasospasm , 2007 .

[25]  S. N. Murthy,et al.  Analysis of Pulmonary Vasodilator Responses to SB-772077-B [4-(7-((3-Amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine], a Novel Aminofurazan-Based Rho Kinase Inhibitor , 2009, Journal of Pharmacology and Experimental Therapeutics.

[26]  A. Takeshita,et al.  Long-Term Inhibition of Rho-Kinase Suppresses Left Ventricular Remodeling After Myocardial Infarction in Mice , 2004, Circulation.

[27]  J. Liao,et al.  Rho Kinase (ROCK) Inhibitors , 2007, Journal of cardiovascular pharmacology.

[28]  Hiroaki Shimokawa,et al.  Development of Rho-kinase inhibitors for cardiovascular medicine. , 2007, Trends in pharmacological sciences.

[29]  B. Berk,et al.  Cyclophilin A Is Secreted by a Vesicular Pathway in Vascular Smooth Muscle Cells , 2006, Circulation research.

[30]  A. Daugherty,et al.  Angiotensin II-mediated development of vascular diseases. , 2004, Trends in cardiovascular medicine.

[31]  A Daugherty,et al.  Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. , 2000, The Journal of clinical investigation.

[32]  M. Yamagishi,et al.  C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats. , 2004, American journal of respiratory and critical care medicine.

[33]  K. Kaibuchi,et al.  Long-Term Inhibition of Rho-kinase Ameliorates Hypoxia-Induced Pulmonary Hypertension in Mice , 2006, Journal of cardiovascular pharmacology.

[34]  G. Rao,et al.  Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. , 1992, Circulation research.

[35]  N. Fukagawa,et al.  Age-related changes in redox signaling and VSMC function. , 2010, Antioxidants & redox signaling.

[36]  A. Takeshita,et al.  Long-Term Inhibition of Rho-Kinase Suppresses Angiotensin II–Induced Cardiovascular Hypertrophy in Rats In Vivo: Effect on Endothelial NAD(P)H Oxidase System , 2003, Circulation research.

[37]  H. Shimokawa Rho-kinase as a Novel Therapeutic Target in Treatment of Cardiovascular Diseases , 2002, Journal of cardiovascular pharmacology.

[38]  P. Ganz,et al.  Angiotensin II Stimulation of Vascular Smooth Muscle Phosphoinositide Metabolism State of the Art Lecture , 1987, Hypertension.

[39]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[40]  H. Shimokawa,et al.  Cyclophilin A: promising new target in cardiovascular therapy. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[41]  H. Fujita,et al.  Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[42]  Chen Yan,et al.  Cyclophilin A Mediates Vascular Remodeling by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation , 2008, Circulation.

[43]  A. Hall,et al.  Rho GTPases* , 1998, The Journal of Biological Chemistry.

[44]  A. Takeshita,et al.  Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta. , 1997, Circulation.

[45]  A. Ridley,et al.  RhoE Binds to ROCK I and Inhibits Downstream Signaling , 2003, Molecular and Cellular Biology.

[46]  Shuh Narumiya,et al.  Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension , 1997, Nature.

[47]  A. Takeshita,et al.  Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. , 1996, The Journal of clinical investigation.

[48]  K. Node,et al.  Molecular basis of restenosis and novel issues of drug-eluting stents. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[49]  S. Umemura,et al.  PJ-247 Early, Simple, Noninvasive Predictors of Left Main or 3-Vessel Disease in Patients with Non-ST-segment Elevation Acute Coronary Syndromes(PJ042,ACS/AMI (Clinical/Diagnosis) 1 (IHD),Poster Session (Japanese),The 73rd Annual Scientific Meeting of The Japanese Circulation Society) , 2009 .

[50]  E. Solary,et al.  Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner , 2005, The Journal of experimental medicine.

[51]  R. Ross,et al.  Atherosclerosis is an inflammatory disease. , 1998, American heart journal.

[52]  H. Shimokawa,et al.  Cellular and molecular mechanisms of coronary artery spasm: lessons from animal models. , 2000, Japanese circulation journal.

[53]  K. Krause,et al.  NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II , 2007, Hypertension.

[54]  P. Pacaud,et al.  The role of Rho protein signaling in hypertension , 2010, Nature Reviews Cardiology.

[55]  B. Berk,et al.  Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells. , 1995, Circulation research.

[56]  K. Sunagawa,et al.  Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure , 2005, Circulation.

[57]  K. Griendling,et al.  Reactive oxygen species in the vasculature: molecular and cellular mechanisms. , 2003, Hypertension.

[58]  C. Yan,et al.  Cyclophilin A is a secreted growth factor induced by oxidative stress. , 2000, Circulation research.

[59]  P. Libby Inflammation in Atherosclerosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[60]  澤田 直樹 Inhibition of Rho-Associated Kinase Results in Suppression of Neointimal Formation of Balloon-Injured Arteries , 2001 .

[61]  A. Takeshita,et al.  Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. , 1999, Cardiovascular research.

[62]  P. Pacaud,et al.  Rho kinases in cardiovascular physiology and pathophysiology. , 2006, Circulation research.

[63]  Liang Xie,et al.  Cyclophilin A Is a Proinflammatory Cytokine that Activates Endothelial Cells , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[64]  Zhenbiao Yang,et al.  RHO Gtpases and the Actin Cytoskeleton , 2000 .

[65]  F. Kajiya,et al.  Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo. , 2005, Journal of the American College of Cardiology.

[66]  N. Sugimoto,et al.  Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice. , 2010, The Journal of clinical investigation.

[67]  K. Takeda,et al.  Rho-Kinase Mediates Angiotensin II-Induced Monocyte Chemoattractant Protein-1 Expression in Rat Vascular Smooth Muscle Cells , 2001, Hypertension.

[68]  I. Hisatome,et al.  PJ-276 Unusual Veins Draining into the Left Atrial Chamber : Anatomical Investigation in 100 Autopsied Hearts(PJ047,Arrhythmia, Others (Clinical/Pathophysiology) 3 (A),Poster Session (Japanese),The 73rd Annual Scientific Meeting of The Japanese Circulation Society) , 2009 .

[69]  K. Takeda,et al.  Critical Role of Rho-Kinase and MEK/ERK Pathways for Angiotensin II-Induced Plasminogen Activator Inhibitor Type-1 Gene Expression , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[70]  A. Hall,et al.  Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. , 2002, Genes & development.

[71]  Kenta Ito,et al.  Importance of dual induction tests for coronary vasospasm and ventricular fibrillation in patients surviving out-of-hospital cardiac arrest. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[72]  A. Takeshita,et al.  Evidence for Protein Kinase C-Mediated Activation of Rho- Kinase in a Porcine Model of Coronary Artery Spasm , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[73]  X. Zheng,et al.  ROCK Isoform Regulation of Myosin Phosphatase and Contractility in Vascular Smooth Muscle Cells , 2009, Circulation research.

[74]  J. Bertoglio,et al.  Human Urotensin II–Induced Contraction and Arterial Smooth Muscle Cell Proliferation Are Mediated by RhoA and Rho-Kinase , 2001, Circulation research.

[75]  L. Lim,et al.  A Novel Serine/Threonine Kinase Binding the Ras-related RhoA GTPase Which Translocates the Kinase to Peripheral Membranes (*) , 1995, The Journal of Biological Chemistry.

[76]  T. Yamamoto,et al.  Rho‐associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. , 1996, The EMBO journal.

[77]  E. Sahai,et al.  Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I , 2001, Nature Cell Biology.

[78]  R W Alexander,et al.  Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. , 1994, Circulation research.

[79]  Yoshiharu Matsuura,et al.  Phosphorylation and Activation of Myosin by Rho-associated Kinase (Rho-kinase)* , 1996, The Journal of Biological Chemistry.

[80]  N. Weintraub,et al.  Understanding abdominal aortic aneurysm. , 2009, The New England journal of medicine.

[81]  P. Pacaud,et al.  P2Y(1), P2Y(2), P2Y(4), and P2Y(6) receptors are coupled to Rho and Rho kinase activation in vascular myocytes. , 2000, American journal of physiology. Heart and circulatory physiology.

[82]  K. Ahn,et al.  Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages. , 2005, Clinical immunology.

[83]  A. Takeshita,et al.  Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo. , 2001, Cardiovascular research.

[84]  N. Weintraub,et al.  Deletion of p47phox Attenuates Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E–Deficient Mice , 2006, Circulation.

[85]  Min Zhang,et al.  NADPH oxidase signaling and cardiac myocyte function. , 2009, Journal of molecular and cellular cardiology.

[86]  Kozo Kaibuchi,et al.  Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase) , 1996, Science.

[87]  A. Takeshita,et al.  Involvement of Rho‐kinase in hypertensive vascular disease —a novel therapeutic target in hypertension , 2001, Fukuoka igaku zasshi = Hukuoka acta medica.

[88]  P. D. de Tombe,et al.  Functional Effects of Rho-Kinase–Dependent Phosphorylation of Specific Sites on Cardiac Troponin , 2005, Circulation research.

[89]  Yoshihisa Okamoto,et al.  Inflammation in atherosclerosis: transition from theory to practice. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

[90]  B. Berk,et al.  Cyclophilin A Promotes Cardiac Hypertrophy in Apolipoprotein E–Deficient Mice , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[91]  P. Kadowitz,et al.  Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[92]  宮田 健二 Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo , 2001 .

[93]  S. Narumiya,et al.  Targeted Disruption of the Mouse Rho-Associated Kinase 2 Gene Results in Intrauterine Growth Retardation and Fetal Death , 2003, Molecular and Cellular Biology.

[94]  K. Kaibuchi,et al.  Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats , 2004, Circulation research.

[95]  S. N. Murthy,et al.  Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat. , 2010, American journal of physiology. Heart and circulatory physiology.

[96]  K. Kaibuchi,et al.  Small GTP-binding proteins. , 1992, International review of cytology.

[97]  R. Ricci,et al.  Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase , 2005, Nature Medicine.

[98]  A. Bernards GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. , 2003, Biochimica et biophysica acta.

[99]  H Shimokawa,et al.  Primary endothelial dysfunction: atherosclerosis. , 1999, Journal of molecular and cellular cardiology.

[100]  F. Luscinskas,et al.  ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. , 2008, The Journal of clinical investigation.

[101]  K. Kohama,et al.  Inhibitory effects of ML-9, wortmannin, and Y-27632 on the chemotaxis of vascular smooth muscle cells in response to platelet-derived growth factor-BB. , 2000, Journal of biochemistry.

[102]  H. Shimokawa,et al.  Rho-Kinase Mediates Hypoxia-Induced Downregulation of Endothelial Nitric Oxide Synthase , 2002, Circulation.

[103]  H. Shimokawa,et al.  Antiischemic properties of fasudil in experimental models of vasospastic angina. , 2001, Japanese journal of pharmacology.

[104]  D. Kass,et al.  Role of oxidative stress in cardiac hypertrophy and remodeling. , 2007, Hypertension.

[105]  A. Daugherty,et al.  Differential Effects of Doxycycline, a Broad-Spectrum Matrix Metalloproteinase Inhibitor, on Angiotensin II–Induced Atherosclerosis and Abdominal Aortic Aneurysms , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[106]  K. Tanaka,et al.  Coronary artery spasm induced in atherosclerotic miniature swine. , 1983, Science.

[107]  H. Shimokawa,et al.  Effects of Rho-kinase inhibitor on vasopressin-induced chronic myocardial damage in rats. , 2002, Life sciences.

[108]  A. Takeshita,et al.  Suppression of Coronary Artery Spasm by the Rho-Kinase Inhibitor Fasudil in Patients With Vasospastic Angina , 2002, Circulation.

[109]  K. Sugamura,et al.  Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. , 2009, Cardiovascular research.

[110]  M. Bukrinsky,et al.  Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A , 2007, Journal of leukocyte biology.

[111]  H. Shimokawa,et al.  Antianginal effects of hydroxyfasudil, a Rho‐kinase inhibitor, in a canine model of effort angina , 2001, British journal of pharmacology.

[112]  A. Hall,et al.  Rho GTPases in cell biology , 2002, Nature.

[113]  S. Hosoda,et al.  Anti-anginal Effect of Fasudil, a Rho-Kinase Inhibitor, in Patients With Stable Effort Angina: A Multicenter Study , 2002, Journal of cardiovascular pharmacology.

[114]  M. Wolin,et al.  Inhibition of coronary artery superoxide dismutase attenuates endothelium-dependent and -independent nitrovasodilator relaxation. , 1991, Circulation research.

[115]  K. Kaibuchi,et al.  Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. , 2001, Trends in pharmacological sciences.

[116]  John G. Collard,et al.  Activation of RhoA by Thrombin in Endothelial Hyperpermeability: Role of Rho Kinase and Protein Tyrosine Kinases , 2000, Circulation research.

[117]  K. Kaibuchi,et al.  Formation of Actin Stress Fibers and Focal Adhesions Enhanced by Rho-Kinase , 1997, Science.

[118]  B. Baxter,et al.  MMP Inhibition in Abdominal Aortic Aneurysms: Rationale for a Prospective Randomized Clinical Trial , 1999, Annals of the New York Academy of Sciences.

[119]  P. Zhu,et al.  Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis , 2008, Rheumatology.

[120]  L. Shimoda,et al.  Ca2+ signaling in hypoxic pulmonary vasoconstriction: effects of myosin light chain and Rho kinase antagonists. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[121]  G. FitzGerald,et al.  Oxidative stress and cardiovascular injury: Part II: animal and human studies. , 2003, Circulation.

[122]  Kenta Ito,et al.  Enhanced Rho-kinase activity in circulating neutrophils of patients with vasospastic angina: a possible biomarker for diagnosis and disease activity assessment. , 2011, Journal of the American College of Cardiology.

[123]  S. N. Murthy,et al.  Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in L-NAME-treated rats. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[124]  J. Liao,et al.  Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease. , 2011, Trends in pharmacological sciences.

[125]  K. Griendling,et al.  Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. , 2007, American journal of physiology. Cell physiology.

[126]  P. Zhu,et al.  Contribution of Cyclophilin A to the Regulation of Inflammatory Processes in Rheumatoid Arthritis , 2009, Journal of Clinical Immunology.

[127]  T. Murohara,et al.  Adiponectin and cardiovascular disease. , 2009, Circulation journal : official journal of the Japanese Circulation Society.

[128]  P. Stern,et al.  Rho and Rho Kinase Are Involved in Parathyroid Hormone‐Stimulated Protein Kinase C α Translocation and IL‐6 Promoter Activity in Osteoblastic Cells , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[129]  B. Berk Vascular smooth muscle growth: autocrine growth mechanisms. , 2001, Physiological reviews.

[130]  J. Liao,et al.  Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[131]  HiroakiShimokawa,et al.  Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation After Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms , 2004 .

[132]  I. Komuro,et al.  Angiotensin II Induces Premature Senescence of Vascular Smooth Muscle Cells and Accelerates the Development of Atherosclerosis via a p21-Dependent Pathway , 2006, Circulation.

[133]  R. Alexander Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. , 1995, Hypertension.

[134]  V. Abramov,et al.  Cyclophilin A produced by thymocytes regulates the migration of murine bone marrow cells. , 2007, Cellular immunology.

[135]  W. Hsueh,et al.  Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice. , 2003, The Journal of clinical investigation.

[136]  K. Nakao,et al.  ROCK‐I and ROCK‐II, two isoforms of Rho‐associated coiled‐coil forming protein serine/threonine kinase in mice , 1996, FEBS letters.

[137]  A. Takeshita,et al.  Involvement of Rho-Kinase in Agonists-Induced Contractions of Arteriosclerotic Human Arteries , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[138]  A. Takeshita,et al.  Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. , 2004, Journal of molecular and cellular cardiology.

[139]  H. Hidaka,et al.  Mechanism of action of a novel antivasospasm drug, HA1077. , 1987, The Journal of pharmacology and experimental therapeutics.

[140]  T. Yamakawa,et al.  Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. , 2000, Hypertension.

[141]  J. Abe,et al.  Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E–deficient mice , 2011, The Journal of experimental medicine.

[142]  A. Villarroel,et al.  New Roles of Myosin II during Vesicle Transport and Fusion in Chromaffin Cells* , 2004, Journal of Biological Chemistry.

[143]  A. Takeshita,et al.  Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice , 2004, Circulation research.

[144]  M. Morimatsu,et al.  Role of Rho-Associated Kinase in Neointima Formation After Vascular Injury , 2001, Circulation.

[145]  P. Vanhoutte Endothelium-derived free radicals: for worse and for better. , 2001, The Journal of clinical investigation.