Preview

Артериальная гипертензия

Расширенный поиск

RHO-КИНАЗА КАК КЛЮЧЕВОЙ УЧАСТНИК РЕГУЛЯЦИИ ТОНУСА СОСУДОВ В НОРМЕ И ПРИ СОСУДИСТЫХ РАССТРОЙСТВАХ

https://doi.org/10.18705/1607-419X-2017-23-5-383-394

Полный текст:

Аннотация

Rho-киназа участвует в регуляции функций практически всех клеток нашего организма. Ключевым активатором Rho-киназы является малый гуанозинтрифосфат (ГТФ)-связывающий белок RhoA, но существуют и RhoA-независимые механизмы регуляции этого фермента. В данном обзоре рассмотрены механизмы, влияющие на активность Rho-киназы в гладкой мышце и эндотелии сосудов, ее роль в регуляции фундаментальных физиологических процессов в этих клетках, а также участие в патогенезе сосудистых расстройств при таких заболеваниях, как системная и легочная артериальная гипертензия и сахарный диабет.

Об авторах

О. С. Тарасова
Федеральное государственное бюджетное  образовательное учреждение высшего образования  «Московский государственный университет  имени М. В. Ломоносова», Москва, Россия  Государственный научный центр Российской Федерации —  Институт медико-биологических проблем РАН.
Россия
Тарасова Ольга Сергеевна — доктор биологических наук, профессор кафедры физиологии человека и животных биологического факультета ФГБОУ ВО МГУ им. М. В. Ломоносова. Ленинские горы, д. 1, стр. 12, Москва, 119234.


Д. К. Гайнуллина
Федеральное государственное бюджетное  образовательное учреждение высшего образования  «Московский государственный университет  имени М. В. Ломоносова», Москва, Россия  Государственный научный центр Российской Федерации —  Институт медико-биологических проблем РАН.
Россия

Гайнуллина Дина Камилевна — кандидат биологических наук, старший научный сотрудник кафедры физиологии человека и животных биологического факультета ФГБОУ ВО МГУ им. М. В. Ломоносова.

Москва.



Список литературы

1. Noma K, Oyama N, Liao JK. Physiological role of ROCKs in the cardiovascular system. Am J Physiol Cell Physiol. 2006;290(3):661–8. doi:10.1152/ajpcell.00459.2005

2. Moreno-Domínguez A, Colinas O, El-Yazbi A, Walsh EJ, Hill MA, Walsh MP et al. Ca2+ sensitization due to myosin light chain phosphatase inhibition and cytoskeletal reorganization in the myogenic response of skeletal muscle resistance arteries. J Physiol. 2013;591(5):1235–50. doi:10.1113/jphysiol.2012.243576

3. Nishimura J, Bi D, Kanaide H. Dependence of proliferating dedifferentiated vascular smooth muscle contraction on Rho-Rho kinase system. Trends Cardiovasc Med. 2006;16(4):124–8. doi:10.1016/j.tcm.2006.02.004

4. Shimizu T, Fukumoto Y, Tanaka SI, Satoh K, Ikeda S, Shimokawa H. Crucial role of ROCK2 in vascular smooth muscle cells for hypoxia-induced pulmonary hypertension in mice. Arterioscler Thromb Vasc Biol. 2013;33(12):2780–91. doi:10.1161/ATVBAHA.113.301357

5. De Silva TM, Kinzenbaw DA, Modrick ML, Reinhardt LD, Faraci FM. Heterogeneous impact of ROCK2 on carotid and cerebrovascular function novelty and significance. Hypertension. 2016;68(3):809–17. doi:10.1161/HYPERTENSIONAHA.116.07430

6. Somlyo AP, Somlyo AV. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev. 2003;83(4):1325–58. doi:10.1152/physrev.00023.2003

7. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-Kinase in the cardiovascular system. Circ Res. 2016;118(2):352–66. doi:10.1161/CIRCRESAHA.115.306532

8. Fujita A, Takeuchi T, Nakajima H, Nishio H, Hata F. Involvement of heterotrimeric GTP-binding protein and rho protein, but not protein kinase C, in agonist-induced Ca2+ sensitization of skinned muscle of guinea pig vas deferens. J Pharmacol Exp Ther. 1995;274(1):555–61.

9. Seasholtz TM, Majumdar M, Brown JH. Rho as a mediator of G protein-coupled receptor signaling. Mol Pharmacol. 1999;55 (6):949–56.

10. Maguore J, Davenport A. Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci. 2005;26(9):448–54. doi:10.1016/j.tips.2005.07.007

11. Sasahara T, Okamoto H, Ohkura N, Kobe A, Yayama K. Epidermal growth factor induces Ca (2+) sensitization through Rho-kinase-dependent phosphorylation of myosin phosphatase target subunit 1 in vascular smooth muscle. Eur J Pharmacol. 2015;762:89–95. doi:10.1016/j.ejphar.2015.05.042

12. Schubert R, Lidington D, Bolz S-S. The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction. Cardiovasc Res. 2008;77(1):8–18. doi:10.1016/j.cardiores. 2007.07.018

13. Sakurada S, Takuwa N, Sugimoto N, Wang Y, Seto M, Sasaki Y et al. Ca2+-dependent activation of Rho and Rho kinase in membrane depolarization-induced and receptor stimulationinduced vascular smooth muscle contraction. Circ Res. 2003;93(6): 548–56. doi:10.1161/01.RES.0000090998.08629.60

14. Urban NH, Berg KM, Ratz PH. K+ depolarization induces RhoA kinase translocation to caveolae and Ca2+ sensitization of arterial muscle. Am J Physiol Cell Physiol. 2003;285(6): C1377–85. doi:10.1152/ajpcell.00501.2002

15. Schleifenbaum J, Kassmann M, Szijarto IA, Hercule HC, Tano J-Y, Weinert S et al. Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries. Circ Res. 2014;115(2):263–72. doi:10.1161/ CIRCRESAHA.115.302882

16. Mederos Y, Schnitzler M, Storch U, Meibers S, Nurwakagari P, Breit A et al. Gq-coupled receptors as mechanosensors mediating myogenic vasoconstriction. EMBO J. 2008;27(23):3092–103. doi:10.1038/emboj.2008.233

17. Koltsova SV, Maximov GV, Kotelevtsev SV, Lavoie JL, Tremblay J, Grygorczyk R et al. Myogenic tone in mouse mesenteric arteries: evidence for P2Y receptor-mediated, Na (+), K (+), 2Cl (-) cotransport-dependent signaling. Purinergic Signal. 2009;5(3): 343–9. doi:10.1007/s11302–009–9160–4

18. Keller M, Lidington D, Vogel L, Peter BF, Sohn H-Y, Pagano PJ et al. Sphingosine kinase functionally links elevated transmural pressure and increased reactive oxygen species formation in resistance arteries. FASEB J. 2006;20(6):702–4. doi:10.1096/ fj.05–4075fje

19. Shimokawa H, Satoh K. 2015 ATVB Plenary Lecture: translational research on rho-kinase in cardiovascular medicine. Arterioscler Thromb Vasc Biol. 2015;35(8):1756–69. doi: 10.1161/ATVBAHA.115.305353

20. Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal. 2013;19(10):1110–20. doi:10.1089/ars.2012.4641

21. Araki S, Ito M, Kureishi Y, Feng J, Machida H, Isaka N et al. Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase. Pflugers Arch. 2001;441(5):596–603

22. Morikage N, Kishi H, Sato M, Guo F, Shirao S, Yano T et al. Cholesterol primes vascular smooth muscle to induce Ca2 sensitization mediated by a sphingosylphosphorylcholineRho-kinase pathway: possible role for membrane raft. Circ Res. 2006;99(3):299–306. doi:10.1161/01.RES.0000235877. 33682.e9

23. Gao Y, Chen Z, Leung SWS, Vanhoutte PM. Hypoxic vasospasm mediated by cIMP: when soluble guanylyl cyclase turns bad. J Cardiovasc Pharmacol. 2015;65(6):545–8. doi:10. 1097/FJC.0000000000000167

24. Воротников А. В., Щербакова О. В., Кудряшова Т. В., Тарасова О. С., Ширинский В. П., Пфитцер Г. и др. Фосфорилирование миозина как основной путь регуляции сокращения гладких мышц. Росс. физиол. журн. им. И. М. Сеченова. 2009;95:1058– 1073. [Vorotnikov AV, Shcherbakova OV, Kudriashova TV, Tarasova OS, Shirinskiĭ VP, Pfitzer G, et al. Myosin phosphorylation as the main way of regulating smooth muscle contractions. Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova = Russian Physiology Journal n. a. IM Sechenov. 2009;95:1058–73. In Russian].

25. Velasco G, Armstrong C, Morrice N, Frame S, Cohen P. Phosphorylation of the regulatory subunit of smooth muscle protein phosphatase 1M at Thr850 induces its dissociation from myosin. FEBS Lett. 2002;527(1–3):101–4.

26. Feng J, Ito M, Ichikawa K, Isaka N, Nishikawa M, Hartshorne DJ et al. Inhibitory phosphorylation site for Rhoassociated kinase on smooth muscle myosin phosphatase. J Biol Chem. 1999;274(52):37385–90.

27. Eto M, Senba S, Morita F, Yazawa M. Molecular cloning of a novel phosphorylation-dependent inhibitory protein of protein phosphatase-1 (CPI17) in smooth muscle: its specific localization in smooth muscle. FEBS Lett. 1997;410(2–3):356–60.

28. Dimopoulos GJ, Semba S, Kitazawa K, Eto M, Kitazawa T. Ca2+-dependent rapid Ca2+ sensitization of contraction in arterial smooth muscle. Circ Res. 2007;100(1):121–9. doi:10.1161/01.RES.0000253902.90489.df

29. Walsh MP, Cole WC. The role of actin filament dynamics in the myogenic response of cerebral resistance arteries. J Cereb Blood Flow Metab 2013;33(1):1–12. doi:10.1038/jcbfm.2012.144

30. Shabir S, Borisova L, Wray S, Burdyga T. Rho-kinase inhibition and electromechanical coupling in rat and guinea- pig ureter smooth muscle: Ca2+-dependent and -independent mechanisms. J Physiol. 2004;560(Pt 3):839–55. doi:10.1113/jphysiol. 2004.070615

31. Villalba N, Stankevicius E, Simonsen U, Prieto D. Rho kinase is involved in Ca2+ entry of rat penile small arteries. Am J Physiol Heart Circ Physiol. 2008;294(4): H1923–32. doi:10.1152/ ajpheart.01221.2007

32. Ghisdal P, Vandenberg G, Morel N. Rho-dependent kinase is involved in agonist-activated calcium entry in rat arteries. J Physiol. 2003;551(Pt 3):855–67. doi:10.1113/jphysiol. 2003.047050

33. Li Y, Brayden JE. Rho kinase activity governs arteriolar myogenic depolarization. J Cereb Blood Flow Metab. 2017;37 (1): 140–52. doi: 10.1177/0271678X15621069

34. Puzdrova VA, Kudryashova TV, Gaynullina DK, Mochalov SV, Aalkjaer C, Nilsson H et al. Trophic action of sympathetic nerves reduces arterial smooth muscle Ca (2+) sensitivity during early post-natal development in rats. Acta Physiol (Oxf). 2014;212 (2):128–41. doi:10.1111/apha.12331

35. Мочалов С. В., Каленчук В. У., Гайнуллина Д. К., Воротников А. В., Тарасова О. С. Вклад протеинкиназы C и Rho-киназы в регуляцию рецептор-зависимого сокращения артерий уменьшается с возрастом и не зависит от симпатической иннервации. Биофизика. 2008;53:1102–8. [Mochalov SV, Kalenchuk VU, Gaĭnullina DK, Vorotnikov AV, Tarasova OS. The contribution of protein kinase C and Rho-kinase to the control of the receptor-dependent artery contraction decreases with age independently of sympathetic innervation. Biofizika = Biophysics. 2008;53:1102–8. In Russian].

36. Tourneux P, Chester M, Grover T, Abman SH. Fasudil inhibits the myogenic response in the fetal pulmonary circulation. Am J Physiol Heart Circ Physiol. 2008;295(4): H1505–13. doi:10.1152/ajpheart.00490.2008.

37. Dunham-Snary KJ, Hong ZG, Xiong PY, Del Paggio JC, Herr JE, Johri AM et al. A mitochondrial redox oxygen sensor in the pulmonary vasculature and ductus arteriosus. Pflugers Arch. 2016;468(1):43–58. doi:10.1007/s00424–015–1736-y

38. Kajimoto H, Hashimoto K, Bonnet SN, Haromy A, Harry G, Moudgil R et al. Oxygen activates the Rho/Rho-Kinase pathway and induces RhoB and ROCK-1 expression in human and rabbit ductus arteriosus by increasing mitochondria-derived reactive oxygen species: a newly recognized mechanism for sustaining ductal constriction. Circulation. 2007;115(13):1777–88. doi:10.1161/CIRCULATIONAHA.106.649566

39. Ширинский В. П. Молекулярная физиология эндотелия и механизмы проницаемости сосудов. Успехи физиол. наук. 2011;42:18–32 [Shirinskiĭ VP. [Molecular physiology of the endothelium and mechanisms of vascular permeability]. Uspekhi Fiziologicheskikh Nauk = Successes of Physiology Science. 2011;42:18–32. In Russian].

40. Гайнуллина Д. К., Кирюхина О. О., Тарасова О. С. Оксид азота в эндотелии сосудов: регуляция продукции и механизмы действия. Успехи физиол. Наук. 2013;44:88–102. [Gaynullina DK, Kiryuhina OO, Tarasova OS. Nitric oxide in vascular endothelium: control of production and mechanisms of action. Uspekhi Fiziologicheskikh Nauk = Successes of Physiology Science. 2013; 44:88–102. In Russian].

41. Fleming I. Molecular mechanisms underlying the activation of eNOS. Pflugers Arch. 2010;459(6):793–806. doi:10.1007/s00424–009–0767–7

42. Sugimoto M, Nakayama M, Goto TM, Amano M, Komori K, Kaibuchi K. Rho-kinase phosphorylates eNOS at threonine 495 in endothelial cells. Biochem Biophys Res Commun. 2007;361 (2): 462–7. doi:10.1016/j.bbrc.2007.07.030

43. Ming X-F, Viswambharan H, Barandier C, Ruffieux J, Kaibuchi K, Rusconi S 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(24):8467–77.

44. Noda K, Nakajima S, Godo S, Saito H, Ikeda S, Shimizu T et al. Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice. PLoS One. 2014;9(11): e110446. doi:10.1371/journal.pone.0110446

45. Church JE, Qian J, Kumar S, Black SM, Venema RC, Papapetropoulos A et al. Inhibition of endothelial nitric oxide synthase by the lipid phosphatase PTEN. Vascul Pharmacol. 2010;52(5–6):191–8. doi:10.1016/j.vph.2009.11.007

46. Li Z, Dong X, Dong X, Wang Z, Liu W, Deng N et al. Regulation of PTEN by Rho small GTPases. Nat Cell Biol. 2005;7 (4):399–404. doi:10.1038/ncb1236

47. Eto M, Barandiér C, Rathgeb L, Kozai T, Joch H, Yang Z 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;89(7):583–90.

48. Pandey D, Bhunia A, Oh YJ, Chang F, Bergman Y, Kim JH et al. OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase. Circ Res. 2014;115(4):450–9. doi:10.1161/CIRCRESAHA.115.304262

49. Huveneers S, Daemen MJAP, Hordijk PL. Between Rho (k) and a hard place: the relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res. 2015;116(5):895–908. doi:10.1161/CIRCRESAHA.116.305720

50. Skaria T, Bachli E, Schoedon G. Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells. Cell Adh Migr. 2017;11(1):24–38. doi:10.1080/19336918. 2016.1178449

51. Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Hiroki J et al. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 2001;15(6):1062–4.

52. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389(6654):990–4. doi:10.1038/40187

53. Loirand G, Pacaud P. Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension. Small GTPases. 2014;5(4):1–10. doi:10.4161/sgtp.28846

54. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H et al. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med. 2005;171(5):494–9. doi:10.1164/rccm.200405– 637OC

55. Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol. 2004;287(4): L665–72. doi:10.1152/ajplung. 00050.2003

56. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK. Rhokinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation. 2002;106(1):57–62.

57. Wojciak-Stothard B, Tsang LYF, Paleolog E, Hall SM, Haworth SG. Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2006;290(6): L1173–82. doi:10.1152/ajplung.00309.2005

58. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y et al. Long-term treatment with a Rhokinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 2004;94(3):385–93. doi:10.1161/01. RES.0000111804.34509.94

59. Ziino AJA, Ivanovska J, Belcastro R, Kantores C, Xu EZ, Lau M et al. Effects of rho-kinase inhibition on pulmonary hypertension, lung growth, and structure in neonatal rats chronically exposed to hypoxia. Pediatr Res. 2010;67(2):177–82. doi:10.1203/ PDR.0b013e3181c6e5a7

60. Do e Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M et al. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J. 2009;73(9):1731–9.

61. Ishikura K, Yamada N, Ito M, Ota S, Nakamura M, Isaka N et al. Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension. Circ J. 2006;70(2):174–8.

62. Болеева Г., Мочалов С., Тарасова О. Функциональные изменения артериальных сосудов при экспериментальном сахарном диабете 1-го типа. Успехи физиол. наук. 2014;45:20–36. [Boleeva GS, Mochalov S V, Tarasova OS. Functional alterations of the arterial vessels in experimental models of type 1 diabetes mellitus. Uspekhi Fiziologicheskikh Nauk = Successes of Physiology Science. 2014;45:20–36. In Russian].

63. Cicek FA, Kandilci HB, Turan B. Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta. Cardiovasc Diabetol. 2013;12:51. doi:10.1186/ 1475–2840–12–51.

64. Hofni A, Shehata Messiha BA, Mangoura SA. Fasudil ameliorates endothelial dysfunction in streptozotocin-induced diabetic rats: a possible role of Rho kinase. Naunyn Schmiedebergs Arch Pharmacol. 2017;390(8):801–811. doi:10.1007/s00210–017– 1379-y

65. Yuan D, Xu S, He P. Enhanced permeability responses to inflammation in streptozotocin-induced diabetic rat venules: Rho-mediated alterations of actin cytoskeleton and VE-cadherin. Am J Physiol Heart Circ Physiol. 2014;307(1): H44–53. doi:10.1152/ajpheart.00929.2013

66. Zhao X-Y, Wang X-F, Li L, Zhang L, Shen D-L, Li D-H et al. Effects of high glucose on human umbilical vein endothelial cell permeability and myosin light chain phosphorylation. Diabetol Metab Syndr. 2015;7:98. doi:10.1186/s13098–015–0098–0

67. Yao L, Chandra S, Toque HA, Bhatta A, Rojas M, Caldwell RB et al. Prevention of diabetes-induced arginase activation and vascular dysfunction by Rho kinase (ROCK) knockout. Cardiovasc Res. 2013;97(3):509–19. doi:10.1093/cvr/cvs371

68. Rao MY, Soliman H, Bankar G, Lin G, MacLeod KM. Contribution of Rho kinase to blood pressure elevation and vasoconstrictor responsiveness in type 2 diabetic Goto- Kakizaki rats. J Hypertens. 2013;31(6):1160–9. doi:10.1097/HJH.0b013e328360383a

69. Matsumoto T, Kobayashi T, Ishida K, Taguchi K, Kamata K. Enhancement of mesenteric artery contraction to 5-HT depends on Rho kinase and Src kinase pathways in the ob/ob mouse model of type 2 diabetes. Br J Pharmacol. 2010;160 (5):1092–104. doi:10.1111/j.1476–5381.2010.00753.x

70. Matsumoto T, Watanabe S, Taguchi K, Kobayashi T. Mechanisms underlying increased serotonin-induced contraction in carotid arteries from chronic type 2 diabetic Goto-Kakizaki rats. Pharmacol Res. 2014;87:123–32. doi:10.1016/j.phrs.2014.07.001

71. Didion SP, Lynch CM, Baumbach GL, Faraci FM. Impaired endothelium-dependent responses and enhanced influence of Rhokinase in cerebral arterioles in type II diabetes. Stroke. 2005;36 (2):342–7. doi: 10.1161/01.STR.0000152952.42730.92

72. Kold-Petersen H, Brøndum E, Nilsson H, Flyvbjerg A, Aalkjaer C. Impaired myogenic tone in isolated cerebral and coronary resistance arteries from the goto-kakizaki rat model of type 2 diabetes. J Vasc Res. 2012;49(3):267–78. doi:10.1159/000335487

73. Nobe K, Hashimoto T, Honda K. Two distinct dysfunctions in diabetic mouse mesenteric artery contraction are caused by changes in the Rho A-Rho kinase signaling pathway. Eur J Pharmacol. 2012;683(1–3):217–25. doi:10.1016/j.ejphar.2012.03.022

74. Дедов И. И., Шестакова М. В. Сахарный диабет и артериальная гипертензия. М.: ООО Медицинское информационное агентство, 2006. [Dedov II, Shestakova M V. Diabetes mellitus and arterial hypertension. M.: Medical Information Agency, 2006. In Russian].

75. Liu L, Tan L, Lai J, Li S, Wang DW. Enhanced Rho-kinase activity: pathophysiological relevance in type 2 diabetes. Clin Chim Acta. 2016;462:107–10. doi:10.1016/j.cca.2016.09.003

76. Suzuki J, Jin ZG, Meoli DF, Matoba T, Berk BC. Cyclophilin A. Is secreted by a vesicular pathway in vascular smooth muscle cells. Circ Res. 2006;98(6):811–7. doi:10.1161/01.RES.0000216405.85080.a6

77. Defert O, Boland S. Rho kinase inhibitors: a patent review (2014–2016). Expert Opin Ther Pat. 2017;27(4):507–15. doi:10.1080/ 13543776.2017.1272579

78. Feng Y, LoGrasso PV, Defert O, Li R. Rho Kinase (ROCK) inhibitors and their therapeutic potential. J Med Chem. 2016;59 (6):2269–300. doi:0.1021/acs.jmedchem.5b00683


Для цитирования:


Тарасова О.С., Гайнуллина Д.К. RHO-КИНАЗА КАК КЛЮЧЕВОЙ УЧАСТНИК РЕГУЛЯЦИИ ТОНУСА СОСУДОВ В НОРМЕ И ПРИ СОСУДИСТЫХ РАССТРОЙСТВАХ. Артериальная гипертензия. 2017;23(5):383-394. https://doi.org/10.18705/1607-419X-2017-23-5-383-394

For citation:


Tarasova O.S., Gaynullina D.K. RHO-KINASE AS A KEY PARTICIPANT IN THE REGULATION OF VASCULAR TONE IN NORMAL CIRCULATION AND VASCULAR DISORDERS. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2017;23(5):383-394. (In Russ.) https://doi.org/10.18705/1607-419X-2017-23-5-383-394

Просмотров: 13


Creative Commons License
Контент доступен под лицензией Creative Commons Attribution 4.0 License.


ISSN 1607-419X (Print)
ISSN 2411-8524 (Online)