Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Expert Opinion on Therapeutic Targets

Volumn 16, Issue 4, 2012, Pages 355-363

  Antoniu, Sabina Antonela ^a  

^a GRIGORE T POPA UNIVERSITY OF MEDICINE AND PHARMACY   (Romania)

Author keywords

angiotensin II; fasudil; pulmonary hypertension; rho kinase; rho kinase inhibitors; simvastatin

Indexed keywords

[1 [(2 DIMETHYLAMINO)ETHYLAMINO] 4 (HYDROXYMETHYL) 7 [(4 METHYLPHENYL)SULFONYL OXYL] 9H XANTHENE 9 ONE]; ANGIOTENSIN CONVERTING ENZYME 2; ANGIOTENSIN II; CASPASE 3; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENDOTHELIN 1; FASUDIL; FURAZAN DERIVATIVE; HYDROXYFASUDIL; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1BETA; LOSARTAN; MYOSIN LIGHT CHAIN; PLATELET DERIVED GROWTH FACTOR; PROTEIN KINASE C; RHO KINASE; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; SB 772077 B; SB 772077B; SEROTONIN ANTAGONIST; SILDENAFIL; SIMVASTATIN; UNCLASSIFIED DRUG; VARDENAFIL; XNT;

APOPTOSIS; BRAIN; CATALYSIS; CELL ADHESION; CELL CYCLE S PHASE; CELL DIVISION; CELL GROWTH; CELL MATURATION; CELL MIGRATION; CELL SURVIVAL; CHROMOSOME 18; CHROMOSOME 2; DENDRITIC CELL; DISEASE DURATION; DISEASE SEVERITY; DRUG TARGETING; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM CELL; GLYCOSYLATION; HEART; HUMAN; LIVER; LUNG; LUNG ARTERY PRESSURE; NONHUMAN; OMPHALOCELE; OUTCOME ASSESSMENT; PATHOGENESIS; POLARIZATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; PULMONARY HYPERTENSION; REVIEW; SIGNAL TRANSDUCTION; SKELETAL MUSCLE; SPLEEN; SYSTOLIC BLOOD PRESSURE; TESTIS; THROMBOSIS; UPREGULATION; VASOCONSTRICTION; VASOSPASM;

ANIMALS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERTENSION, PULMONARY; PHOSPHODIESTERASE 5 INHIBITORS; PROTEIN KINASE INHIBITORS; RHO-ASSOCIATED KINASES; RHOA GTP-BINDING PROTEIN; SIGNAL TRANSDUCTION;

EID: 84859607472     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2012.671811     Document Type: Review

References (58)

1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36
2. Barst RJ, Ertel SI, Beghetti M, Ivy DD. Pulmonary arterial hypertension: a comparison between children and adults. Eur Respir J 2011;37:665-77
3. Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 1996;392:189-93 (Pubitemid 26276745)
4. Amano M, Nakayama M, Kaibuchi K. Rho-kinase/rock: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton (Hoboken) 2010;67:545-54
5. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98:322-34 An excellent review on the roles of RhoA-ROCK system in cardiovascular physiology.
6. Leung T, Chen XQ, Manser E, Lim L. The p160 RhoA-binding kinase ROKalpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol 1996;16:5313-27 (Pubitemid 26315050)
7. Matsui T, Amano M, Yamamoto T, et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. Embo J 1996;15:2208-16 (Pubitemid 26141137)
8. Narumiya S. The small GTPase Rho: cellular functions and signal transduction. J Biochem 1996;120:215-28 (Pubitemid 26335910)
9. Amano M, Mukai H, Ono Y, et al. Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 1996;271:648-50 (Pubitemid 26052909)
10. Hiroki J, Shimokawa H, Higashi M, et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004;37:537-46 (Pubitemid 38953381)
11. Maekawa M, Ishizaki T, Boku S, et al. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999;285:895-8 (Pubitemid 29381991)
12. Amano M, Chihara K, Kimura K, et al. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 1997;275:1308-11 (Pubitemid 27114159)
13. Somlyo AV. Cyclic GMP regulation of myosin phosphatase: a new piece for the puzzle? Circ Res 2007;101:645-7 (Pubitemid 47494093)
14. Thumkeo D, Keel J, Ishizaki T, et al. Targeted disruption of the mouse Rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol Cell Biol 2003;23:5043-55 (Pubitemid 36793348)
15. Shimizu Y, Thumkeo D, Keel J, et al. ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol 2005;168:941-53 (Pubitemid 40397008)
16. Shimokawa H, Rashid M. Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci 2007;28:296-302 (Pubitemid 46818464)
17. 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
18. Do EZ, Fukumoto Y, Takaki A, et al. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J 2009;73:1731-9 An excellent paper on the role of RhoA-ROCK in PAH pathogenesis.
19. Guilluy C, Rolli-Derkinderen M, Tharaux PL, et al. Transglutaminase- dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 2007;282:2918-28 (Pubitemid 47084345)
20. Liu AJ, Ling F, Wang D, et al. Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip1 via the ERK signal pathway. Chin Med J (Engl) 2011;124:3098-104
21. Wang Z, Jin N, Ganguli S, et al. Rho-kinase activation is involved in hypoxia-induced pulmonary vasoconstriction. Am J Respir Cell Mol Biol 2001;25:628-35 A paper on the role of ROCK in hypoxemic pulmonary hypertension. (Pubitemid 33087114)
22. Nagaoka T, Gebb SA, Karoor V, et al. Involvement of rhoa/rho kinase signaling in pulmonary hypertension of the fawn-hooded rat. J Appl Physiol 2006;100:996-1002 (Pubitemid 43671557)
23. Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. Faseb J 2001;15:427-38 (Pubitemid 32141434)
24. Oka M, Homma N, Taraseviciene-Stewart L, et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 2007;100:923-9 (Pubitemid 46555698)
25. Godin CM, Ferguson SS. The angiotensin II type 1 receptor induces membrane blebbing by coupling to Rho A, Rho kinase, and myosin light chain kinase. Mol Pharmacol 77:903-11
26. Lima VV, Giachini FR, Carneiro FS, et al. O-GlcNAcylation contributes to the vascular effects of ET-1 via activation of the RhoA/Rho-kinase pathway. Cardiovasc Res 2011;89:614-22
27. Takemoto M, Sun J, Hiroki J, et al. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitricoxide synthase. Circulation 2002;106:57-62 (Pubitemid 34747442)
28. Schwenke DO, Pearson JT, Sonobe T, et al. Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension. J Appl Physiol 2011;110:901-8
29. Xu EZ, Kantores C, Ivanovska J, et al. Rescue treatment with a rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension. Am J Physiol Heart Circ Physiol 2010;299:H1854-64
30. Chen XY, Dun JN, Miao QF, Zhang YJ. Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses 5-hydroxytryptamine-induced pulmonary artery smooth muscle cell proliferation via JNK and ERK1/2 pathway. Pharmacology 2009;83:67-79 A paper on the vasodilator roles of fasudil a specific ROCK inhibitor.
31. Fagan KA, Oka M, Bauer NR, et al. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol 2004;287:L656-64 (Pubitemid 39249378)
32. Yasuda T, Tada Y, Tanabe N, et al. Rho-kinase inhibition alleviates pulmonary hypertension in transgenic mice expressing a dominant-negative type 2 bone morphogenetic protein receptor gene. Am J Physiol Lung Cell Mol Physiol 2011;301:L667-74
33. Abe K, Shimokawa H, Morikawa K, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res 2004;94:385-93 A paper on long-term effects of fasudil in pulmonary hypertension. (Pubitemid 38240731)
34. Abe K, Tawara S, Oi K, et al. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol 2006;48:280-5 (Pubitemid 46066832)
35. Weigand L, Sylvester JT, Shimoda LA. Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 2006;290:L284-90
36. Guilluy C, Sauzeau V, Rolli-Derkinderen M, et al. Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. Br J Pharmacol 2005;146:1010-18 (Pubitemid 41722174)
37. Li F, Xia W, Li A, et al. Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats. Pharmacol Res 2007;55:64-71 (Pubitemid 46108589)
38. Nagaoka T, Fagan KA, Gebb SA, et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171:494-9 (Pubitemid 40444250)
39. 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 (Pubitemid 40299237)
40. Fujita H, Fukumoto Y, Saji K, et al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels 2010;25:144-9
41. Doe C, Bentley R, Behm DJ, et al. Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. J Pharmacol Exp Ther 2007;320:89-98 (Pubitemid 46025723)
42. Dhaliwal JS, Badejo AM Jr, Casey DB, 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. J Pharmacol Exp Ther 2009;330:334-41
43. Failli P, Alfarano C, Franchi-Micheli S, et al. Losartan counteracts the hyper-reactivity to angiotensin II and ROCK1 over-activation in aortas isolated from streptozotocin-injected diabetic rats. Cardiovasc Diabetol 2009;8:32
44. Shatanawi A, Romero MJ, Iddings JA, et al. Angiotensin II-induced vascular endothelial dysfunction through RhoA/ Rho kinase/p38 mitogen-activated protein kinase/arginase pathway. Am J Physiol Cell Physiol 2011;300:C1181-92
45. Chassagne C, Eddahibi S, Adamy C, et al. Modulation of angiotensin II receptor expression during development and regression of hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol 2000;22:323-32 (Pubitemid 30343359)
46. Bradford CN, Ely DR, Raizada MK. Targeting the vasoprotective axis of the renin-angiotensin system: a novel strategic approach to pulmonary hypertensive therapy. Curr Hypertens Rep 2010;12:212-19
47. Ferreira AJ, Shenoy V, Yamazato Y, et al. Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. Am J Respir Crit Care Med 2009;179:1048-54
48. Xing XQ, Gan Y, Wu SJ, et al. Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway. Med Hypotheses 2007;68:1108-13 A paper on the inhibitory role of statins on ROCK and on its relevance for pulmonary hypertension.
49. Li M, Li Z, Sun X. Statins suppress MMP2 secretion via inactivation of RhoA/ROCK pathway in pulmonary vascular smooth muscles cells. Eur J Pharmacol 2008;591:219-23
50. Ikeda T, Nakamura K, Akagi S, et al. Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. J Cardiovasc Pharmacol 2010;55:39-48
51. Laudi S, Trump S, Schmitz V, et al. Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin. Am J Physiol Lung Cell Mol Physiol 2007;293:L630-8 (Pubitemid 47358825)
52. Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation 2003;108:1640-5 (Pubitemid 37187793)
53. Wilkins MR, Ali O, Bradlow W, et al. Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med 2010;181:1106-13
54. Wu X, Somlyo AV, Somlyo AP. Cyclic GMP-dependent stimulation reverses G-protein-coupled inhibition of smooth muscle myosin light chain phosphatase. Biochem Biophys Res Commun 1996;220:658-63 (Pubitemid 26198568)
55. Sauzeau V, Le Jeune H, Cario-Toumaniantz C, et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 2000;275:21722-9
56. Begum N, Sandu OA, Duddy N. Negative regulation of Rho signaling by insulin and its impact on actin cytoskeleton organization in vascular smooth muscle cells. Diabetes 2002;51:2256-63
57. Morelli A, Filippi S, Sandner P, et al. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med 2009;6:1594-608
58. Li M, Sun X, Li Z, Liu Y. Inhibition of cGMP phosphodiesterase 5 suppresses serotonin signalling in pulmonary artery smooth muscles cells. Pharmacol Res 2009;59:312-18