Targeting Rho and Rho-kinase in the treatment of cardiovascular disease.

The small GTPase Rho and its downstream effector Rho-kinase contribute to agonist-induced vascular contraction via Ca2+ sensitization. Reasonably selective pharmacological inhibitors of these proteins have been developed and are now widely used experimentally to investigate the role of this signaling pathway in vascular function. Rho and Rho-kinase have attracted increasing clinical interest as a result of emerging evidence for their roles in the pathogenesis of several cardiovascular disorders, including hypertension, coronary and cerebral vasospasm, atherosclerosis and diabetes, and are now considered important future therapeutic targets. A major challenge lies in further developing selective inhibitors of this pathway beyond experimental use. Consideration should perhaps also be given to widening the application of existing clinical drugs now known to also interfere with Rho-Rho-kinase signaling.

[1]  P. Vandenabeele,et al.  Tumor necrosis factor-alpha-induced activation of RhoA in airway smooth muscle cells: role in the Ca2+ sensitization of myosin light chain20 phosphorylation. , 2003, Molecular pharmacology.

[2]  K. Chayama,et al.  Smoking Activates Rho-Kinase in Smooth Muscle Cells of Forearm Vasculature in Humans , 2003, Hypertension.

[3]  A. Hall,et al.  Rho GTPases in transformation and metastasis. , 2002, Advances in cancer research.

[4]  A. Takeshita,et al.  Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. , 2000, Circulation.

[5]  F. Faraci,et al.  Impaired Endothelium-Dependent Responses and Enhanced Influence of Rho-Kinase in Cerebral Arterioles in Type II Diabetes , 2005, Stroke.

[6]  D. Hartshorne,et al.  Activation of RhoA and Inhibition of Myosin Phosphatase as Important Components in Hypertension in Vascular Smooth Muscle , 2003, Circulation research.

[7]  G. Nickenig,et al.  Rapid Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition on Coronary Endothelial Function , 2003 .

[8]  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.

[9]  B. Vollrath,et al.  Functional roles of the rho/rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin: relevance to subarachnoid hemorrhage and vasospasm. , 2003, Circulation research.

[10]  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.

[11]  M. Moskowitz,et al.  Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Sigmund,et al.  Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  S. Mathur,et al.  Angiotensin II–Induced Vascular Dysfunction Is Mediated by the AT1A Receptor in Mice , 2004, Hypertension.

[14]  H. Shimokawa,et al.  Usefulness of Fasudil, a Rho-kinase Inhibitor, to Treat Intractable Severe Coronary Spasm after Coronary Artery Bypass Surgery , 2004, Journal of cardiovascular pharmacology.

[15]  M. Moskowitz,et al.  Neuroprotection mediated by changes in the endothelial actin cytoskeleton. , 2000, The Journal of clinical investigation.

[16]  D. Heistad,et al.  Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage. , 2005, American journal of physiology. Heart and circulatory physiology.

[17]  E. Jaimes,et al.  Stable Compounds of Cigarette Smoke Induce Endothelial Superoxide Anion Production via NADPH Oxidase Activation , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[18]  K. Kaibuchi,et al.  The COOH Terminus of Rho-kinase Negatively Regulates Rho-kinase Activity* , 1999, The Journal of Biological Chemistry.

[19]  S. Narumiya,et al.  Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. , 2000, Molecular pharmacology.

[20]  C. Sobey,et al.  Evidence That Rho-Kinase Activity Contributes to Cerebral Vascular Tone In Vivo and Is Enhanced During Chronic Hypertension: Comparison With Protein Kinase C , 2001, Circulation research.

[21]  U. Laufs,et al.  Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. , 1998, Circulation.

[22]  H. Shimokawa,et al.  Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. , 2005, American journal of respiratory and critical care medicine.

[23]  U. Laufs,et al.  Pleiotropic effects of statins. - Basic research and clinical perspectives -. , 2010, Circulation journal : official journal of the Japanese Circulation Society.

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

[25]  J. J. Gibson,et al.  Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  W. März,et al.  Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans , 2005, Circulation.

[27]  J. Liao,et al.  Inhibition of Rho-Kinase Leads to Rapid Activation of Phosphatidylinositol 3-Kinase/Protein Kinase Akt and Cardiovascular Protection , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[28]  N. Kobayashi,et al.  Involvement of Rho-kinase pathway for angiotensin II-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats. , 2002, The Journal of pharmacology and experimental therapeutics.

[29]  S. Venkatesan,et al.  3-Hydroxy-3-methylglutaryl-coenzyme A reductase. The difference in the mechanism of the in vitro modulation by phosphorylation and dephosphorylation to modulation of enzyme activity by non-esterified cholesterol. , 1982, Biochimica et biophysica acta.

[30]  C. Sobey,et al.  Opposing Roles of Endothelial and Smooth Muscle Phosphatidylinositol 3-Kinase in Vasoconstriction: Effects of Rho-Kinase and Hypertension , 2005, Journal of Pharmacology and Experimental Therapeutics.

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

[32]  U. Laufs,et al.  Post-transcriptional Regulation of Endothelial Nitric Oxide Synthase mRNA Stability by Rho GTPase* , 1998, The Journal of Biological Chemistry.

[33]  K. Chayama,et al.  Smoking, Endothelial Function, and Rho-Kinase in Humans , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[34]  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.

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

[36]  U. Laufs,et al.  3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27 Kip1 * , 1999, The Journal of Biological Chemistry.

[37]  B. Vollrath,et al.  Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C. , 2004, American journal of physiology. Heart and circulatory physiology.

[38]  A. Takeshita,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 , 2003, Circulation research.

[39]  J. Downward.  Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[40]  A. Somlyo,et al.  Signal transduction by G‐proteins, Rho‐kinase and protein phosphatase to smooth muscle and non‐muscle myosin II , 2000, The Journal of physiology.

[41]  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.

[42]  C. Sobey,et al.  SUBARACHNOID HAEMORRHAGE: WHAT HAPPENS TO THE CEREBRAL ARTERIES? , 1998, Clinical and experimental pharmacology & physiology.

[43]  K. Krobert,et al.  Dual Serotonergic Regulation of Ventricular Contractile Force Through 5-HT2A and 5-HT4 Receptors Induced in the Acute Failing Heart , 2005, Circulation research.

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

[45]  K. Kaibuchi,et al.  Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo , 2001, Arteriosclerosis, thrombosis, and vascular biology.

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

[47]  M. Takayasu,et al.  Intra-Arterial Infusion of Fasudil Hydrochloride for Treating Vasospasm Following Subarachnoid Haemorrhage , 1999, Acta Neurochirurgica.

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

[49]  J. Montani,et al.  Thrombin Stimulates Human Endothelial Arginase Enzymatic Activity via RhoA/ROCK Pathway: Implications for Atherosclerotic Endothelial Dysfunction , 2004, Circulation.

[50]  Z. Ying,et al.  Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. , 2004, American journal of physiology. Heart and circulatory physiology.

[51]  A. Ortiz,et al.  3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. , 1998, Circulation research.

[52]  C. Sobey,et al.  Evidence That Estrogen Suppresses Rho-Kinase Function in the Cerebral Circulation In Vivo , 2004, Stroke.

[53]  K. Kaibuchi,et al.  Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm. , 2000, Circulation research.

[54]  X. Q. Chen,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 , 1996, Molecular and cellular biology.

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

[56]  J. Liao,et al.  Rho-Kinase Mediates Hyperglycemia-Induced Plasminogen Activator Inhibitor-1 Expression in Vascular Endothelial Cells , 2005, Circulation.

[57]  M. Hirano,et al.  Long-Term Inhibition of RhoA Attenuates Vascular Contractility by Enhancing Endothelial NO Production in an Intact Rabbit Mesenteric Artery , 2005, Circulation research.

[58]  A. Tedgui,et al.  Rho-Associated Protein Kinase Contributes to Early Atherosclerotic Lesion Formation in Mice , 2003, Circulation research.

[59]  K. Kaibuchi,et al.  RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. , 2004, Hypertension research : official journal of the Japanese Society of Hypertension.

[60]  S. Ayral-Kaloustian,et al.  Protein farnesyltransferase inhibitors. , 2002, Current medicinal chemistry.

[61]  C. Sobey,et al.  Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[62]  A. Somlyo,et al.  Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. , 2003, Physiological reviews.