2014 williams harvey lecture: Importance of coronary vasomotion abnormalities - From bench to bedside

European Heart Journal

Volumn 35, Issue 45, 2014, Pages 3180-3193

  Shimokawa, Hiroaki ^a  

^a TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Coronary spasm; Coronary vasomotion; Endothelial cells; Rho kinase; Vascular smooth muscle

Indexed keywords

ENDOTHELIUM DERIVED HYPERPOLARIZING FACTOR; ENDOTHELIUM DERIVED RELAXING FACTOR; HYDROGEN PEROXIDE; MYOSIN LIGHT CHAIN; RHO KINASE; ENDOTHELIAL NITRIC OXIDE SYNTHASE;

BLOOD VESSEL TONE; CARDIOVASCULAR DISEASE; CORONARY ARTERY DISEASE; CORONARY ARTERY SPASM; CORONARY VASOMOTION ABNORMALITY; DISEASE ASSOCIATION; ENDOTHELIAL DYSFUNCTION; HUMAN; ISCHEMIC HEART DISEASE; JAPANESE (PEOPLE); MICROVASCULATURE; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE; VASCULAR SMOOTH MUSCLE CELL HYPERCONTRACTION; VASODILATATION; CARDIOVASCULAR DISEASES; METABOLISM; MUSCLE CONTRACTION; PATHOPHYSIOLOGY; PHOSPHORYLATION; PHYSIOLOGY;

CARDIOVASCULAR DISEASES; CORONARY VASOSPASM; ENDOTHELIUM, VASCULAR; ENDOTHELIUM-DEPENDENT RELAXING FACTORS; HUMANS; MICROVESSELS; MUSCLE CONTRACTION; MUSCLE, SMOOTH, VASCULAR; MYOSIN LIGHT CHAINS; NITRIC OXIDE SYNTHASE TYPE III; PHOSPHORYLATION; RHO-ASSOCIATED KINASES; VASODILATION;

EID: 84922373325     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehu427     Document Type: Review

References (141)

1. Crea F, Camici PG, De Caterina R, Lanza GA. Chronic ischaemic heart disease. In: Camm AJ, Luscher TF, Serruys PW (eds), The ESC Textbook of Cardiovascular Medicine. New York: Oxford University Press; 2009, 596-664.
2. Canty JM Jr. Coronary blood flow and myocardial ischemia. In: Bonow RO, Mann DL, Zipes DP, Libby P (eds), Braunwald's Heart Disease. Philadelphia: Elsevier Saunders; 2012, 1049-1075.
3. Crea F, Lanza GA, Camici PG (eds). Coronary Microvascular Dysfunction. Milan: Springer, 2014, 1-257.
4. Deussen A, OhanyanV, Jannasch A, Yin L,ChilianW. Mechanisms of metabolic coronary flow regulation. J Mol Cell Cardiol 2012;52:794-801.
5. Heusch G, Kleinbongard P, Skyschally A, Levkau B, Schulz R, Erbel R. The coronary circulation in cardioprotection: more than just one confounder. Cardiovasc Res 2012;94:237-245.
6. Duncker DJ, Bache RJ. Regulation of coronary blood flow during exercise. Physiol Rev 2008;88:1009-1086.
7. Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, Indolfi C, Rimoldi O. Alpha-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 2000;101:689-694.
8. Li J, Zhang H, Zhang C. Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications. J Mol Cell Cardiol 2012;52:865-872.
9. Bugiardini R, Bairey Merz CN. Angina with 'normal' coronary arteries: a changing philosophy. JAMA 2005;293:477-484.
10. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886-895.
11. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-376.
12. Vanhoutte PM. Endothelial dysfunction. The first step toward coronary arteriosclerosis. Circ J 2009;73:595-601.
13. Shimokawa H. Primary endothelial dysfunction: atherosclerosis. J Mol Cell Cardiol 1999;31:23-37.
14. Chilian WM, Kuo L, DeFily DV, Jones CJ, Davis MJ. Endothelial regulation of coronary microvascular tone under physiological and pathophysiological conditions. Eur Heart J 1993;14(Suppl I):55-59.
15. Duncker DJ, Bache RJ, Merkus D. Regulation of coronary resistance vessel tone in response to exercise. J Mol Cell Cardiol 2012;52:802-813.
16. Kelm M, Schrader J. Control of coronary vascular tone by nitric oxide. Circ Res 1990; 66:1561-1575.
17. Shimokawa H, Yasutake H, Fujii K, Owada MK, Nakaike R, Fukumoto Y, Takayanagi T, Nagao T, Egashira K, Fujishima M, Takeshita A. The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol 1996;28:703-711.
18. Urakami-Harasawa L, Shimokawa H, Nakashima M, Egashira K, Takeshita A. Importance of endothelium-derived hyperpolarizing factor in human arteries. J Clin Invest 1997;100:2793-2799.
19. Busse R, Edwards G, Feletou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: bringing the concepts together. Trends Pharmacol Sci 2002;23:374-380.
20. Takamura Y, Shimokawa H, Zhao H, Igarashi H, Egashira K, Takeshita A. Important role of endothelium-derived hyperpolarizing factor in shear stress-induced endothelium-dependent relaxations in the rat mesenteric artery. J Cardiovasc Pharmacol 1999;34:381-387.
21. Shimokawa H. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pflug Arch Eur J Physiol 2010;459:915-922.
22. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 1988;93:515-524.
23. Chen G, Suzuki H, Weston AH. Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br J Pharmacol 1988;95: 1165-1174.
24. Campbell WB, Gebremedhin D, Pratt PF, Harder DR. Identification of epoxyeocosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 1996;78: 415-423.
25. Fisslthaler B, Popp R, Kiss L, Potente M, Harder DR, Fleming I, Busse R. Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 1999;401:493-497.
26. Edwards G, Dora KA, Gardener MJ, Garland CJ,Weston AH.K+is an endotheliumderived hyperpolarizing factor in rat arteries. Nature 1998;396:269-272.
27. Griffith TM, Chaytor AT, Edwards DH. The obligatory link: role of gap junctional communication in endothelium-dependent smooth muscle hyperpolarization. Pharmacol Res 2004;49:551-564.
28. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 2000;106:1521-1530.
29. Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kunihiro I, Mukai Y, Hirakawa Y, Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. Biochem Biophys Res Commun 2002; 290:909-913.
30. Matoba T, Shimokawa H, Morikawa K, Kubota H, Kunihiro I, Urakami-Harasawa L, Mukai Y, Hirakawa Y, Akaike T, Takeshita A. Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels. Arterioscler Thromb Vasc Biol 2003;23:1224-1230.
31. Yada T, Shimokawa H, Hiramatsu O, Kajita T, Shigeto F, Goto M, Ogasawara Y, Kajiya F. Hydrogen peroxide, an endogenous endothelium-derived hyperpolarizing factor, plays an important role in coronary autoregulation in vivo. Circulation 2003; 107:1040-1045.
32. Lacza Z, Puskar M, Kis B, Perciaccante JV, Miller AW, BusijaDW. Hydrogen peroxide acts as an EDHF in the piglet pial vasculature in response to bradykinin. Am J Physiol 2002;283:H406-H411.
33. Miura H, Bosnjak JJ, Ning G, Saito T, Miura M, Gutterman DD. Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles. Circ Res 2003; 92:e31-e40.
34. Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder MA, Hatanaka M, Fujiki T, Maeda H, Takahashi S, Takeshita A. Pivotal role of Cu, Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest 2003;112:1871-1879.
35. Morikawa K, Fujiki T, Matoba T, Kubota H, Hatanaka M, Takahashi S, Shimokawa H. Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries. J Cardiovasc Pharmacol 2004;44:552-556.
36. Morishita T, Tsutsui M, Shimokawa H, Sabanai K, Tasaki H, Suda O, Nakata S, Tanimoto A,Wang K-Y, Ueta Y, Sasaguri Y, Nakashima Y, Yanagihara N. Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci USA 2005;102:10616-10621.
37. Takaki A, Morikawa K, Murayama Y, Tekes E, Yamagishi H, Ohashi J, Tsutsui M, Yanagihara N, Yada T, Shimokawa H. Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 2008; 205:2053-2063.
38. Takaki A, Morikawa K, Murayama Y, Yamagishi H, Hosoya M, Ohashi J, Shimokawa H. Roles of endothelial oxidases in endothelium-derived hyperpolarizing factor responses in mice. J Cardiovasc Pharmacol 2008;52:510-517.
39. Prysyazhna O, Rudyk O, Eaton P. Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nat Med 2012;18:286-290.
40. Ohashi J, Sawada A, Nakajima S, Noda K, Takaki A, Shimokawa H. The mechanisms for enhanced endothelium-derived hyperpolarizing factor-mediatedresponses in microvessels in mice. Circ J 2012;76:1768-1779.
41. Nakajima S, Ohashi J, Sawada A, Noda K, Fukumoto Y, Shimokawa H. Essential role of bone marrowfor microvascular endothelial and metabolic functions in mice. Circ Res 2012;111:87-96.
42. Enkhjargal B, Godo S, Sawada A, Suvd N, Saito H, Noda K, Satoh K, Shimokawa H. Endothelial AMPK regulates blood pressure and coronary flow responses through hyperpolarization mechanism in mice. Arterioscler Thromb Vasc Biol 2014;34: 1505-1513.
43. Tagawa H, Shimokawa H, Tagawa T, Kuroiwa-Matsumoto M, Hirooka Y, Takeshita A. Short-Term estrogen augments both nitric oxide-mediated and nonnitric oxide-mediated endothelium-dependent forearm vasodilation in postmenopausal women. J Cardiovasc Pharmacol 1997;30:481-488.
44. Tagawa H, Shimokawa H, Tagawa T, Kuroiwa-Matsumoto M, Hirooka Y, Takeshita A. Long-Term treatment with eicosapentaenoic acid augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilatation in patients with coronary artery disease. J Cardiovasc Pharmacol 1999;33:633-640.
45. Inokuchi K, Hirooka Y, Shimokawa H, Sakai K, Kishi T, Ito K, Kimura Y, Takeshita A. Role of endothelium-derived hyperpolarizing factor in human forearm circulation. Hypertension 2003;42:919-924.
46. Ozkor MA, Murrow JR, Rahman AM, Kavtaradze N, Lin J, Manatunga A, Quyyumi AA. Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. Circulation 2011; 123:2244-2253.
47. Spilk S, Herr MD, Sinoway LI, Leuenberger UA. Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans. Am J Physiol 2013;305:H1639-H1645.
48. Yada T, Shimokawa H, Hiramatsu O, Shinozaki Y, Mori H, Kiyooka T, Goto M, Ogasawara Y, Kajiya F. Cardioprotective role of hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo. Am J Physiol 2006;291:H1138-H1146.
49. Yada T, Shimokawa H, Hiramatsu O, Shinozaki Y, Mori H, Goto M, Ogasawara Y, Kajiya F. Important role of hydrogen peroxide in pacing-induced metabolic coronary vasodilatation in dogs in vivo. J Am Coll Cardiol 2007;50:1271-1278.
50. Tsutsui M, Shimokawa H, Otsuji Y, Yanagihara N. Pathophysiological relevance of NO signaling in the cardiovascular system: novel insight from mice lacking all NO synthases. Pharmacol Ther 2010;128:499-508.
51. Shimokawa H, Tustsui M. Nitric oxide synthases in the pathogenesis of cardiovascular disease. Pflug Arch Eur J Physiol 2010;459:959-967.
52. Maseri A, Severi S, Nes MD, L'Abbate A, Chierchia S, Marzilli M, Ballestra AM, Parodi O, Biagini A, Distante A. 'Variant' angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia: pathogenetic mechanisms, estimated incidence and clinical and coronary angiographic findings in 138 patients. Am J Cardiol 1978;42:1019-1035.
53. Yasue H, Takizawa A, Nagao M, Nishida S, Horie M, Kubota J,Omote S, Takaoka K, Okumura K. Long-Term prognosis for patients with variant angina and influential factors. Circulation 1988;78:1-9.
54. Shimokawa H, Nagasawa K, Irie T, Egashira S, Egashira K, Sagara T, Kikuchi Y, Nakamura M. Clinical characteristics and long-Term prognosis of patients with variant angina. A comparative study between western and Japanese populations. Int J Cardiol 1988;18:331-349.
55. Vanhoutte PM, Shimokawa H. Endothelium-derived relaxing factor(s) and coronary vasospasm. Circulation 1989;80:1-9.
56. Maseri A, Davies G, Hackett D, Kaski JC. Coronary artery spasm and vasoconstriction. The case for a distinction. Circulation 1990;81:1983-1991.
57. Shimokawa H, Tomoike H, Nabeyama S, Yamamoto H, Araki H, Nakamura M, Ishii Y, Tanaka K. Coronary artery spasm induced in atherosclerotic miniature swine. Science 1983;221:560-562.
58. Shimokawa H, Tomoike H, Nabeyama S, Yamamoto H, Ishii Y, Tanaka K, Nakamura M. Coronary artery spasm induced in miniature swine: angiographic evidence and relation to coronary atherosclerosis. Am Heart J 1985;110:300-310.
59. McFadden EP, Bauters C, Lablanche J-M, Quandalle P, Leroy F, Bertland ME. Response of human coronary arteries to serotonin after injury by coronary angioplasty. Circulation 1993;88:2076-2085.
60. Ozaki Y, Keane D, Serruys PW. Progression and regression of coronary stenosis in the long-Term follow-up of vasospastic angina: a quantitative angiographic study. Circulation 1995;92:2446-2456.
61. Shimokawa H, Aarhus LL, Vanhoutte PM. Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin. Circ Res 1987;61:256-270.
62. Shimokawa H, Flavahan NA, Vanhoutte PM. Natural course of the impairment of endothelium-dependent relaxation after balloon endothelium removal in porcine coronary arteries: possible dysfunction of a pertussis toxin-sensitive G-protein. Circ Res 1989;65:740-753.
63. Yamamoto Y, Tomoike H, Egashira K, Nakamura M. Attenuation of endotheliumrelated relaxation and enhanced responsiveness of vascular smooth muscle to histamine in spastic coronary arterial segments from miniature pigs. Circ Res 1987;61: 772-778.
64. Forman MB, Oates JA, Robertson D, Robertson RM, Roberts LJ, Virmani R. Increased adventitial mast cells in a patient with coronary spasm. N Engl J Med 1985;313:1138-1141.
65. Jougasaki M, Yasue H, Takahashi K. Perivascular nerve lesion of the coronary artery involved in spasm in a patient with variant angina. Pathology 1989;21:304-307.
66. Lange RA, Cigarroa RG, Yancy CW Jr, Willard JE, Popma JJ, Sills MN, McBrideW, Kim AS, Hillis LD. Cocaine-induced coronary artery vasoconstriction. N Engl J Med 1989;321:1557-1562.
67. Shimokawa H, Ito A, Fukumoto Y, Kadokami T, Nakaike R, Sakata M, Takayanagi T, Egashira K, Takeshita A. Chronic treatment with interleukin-1b induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. J Clin Invest 1996;97:769-776.
68. Ito A, Shimokawa H, Kadokami T, Fukumoto Y, Owada MK, Shiraishi T, Nakaike R, Takayanagi T, Egashira K, Takeshita A. Tyrosine kinase inhibitor suppresses coronary arteriosclerotic changes and vasospastic responses induced by chronic treatment with interleukin-1b in pigs in vivo. J Clin Invest 1995;96:1288-1294.
69. Ito A, Shimokawa H, FukumotoY, Kadokami T, Nakaike R, TakayanagiT, Egashira K, Sueishi K, Takeshita A. The role of fibroblast growth factor-2 in the vascular effects of interleukin-1b in porcine coronary arteries in vivo. Cardiovasc Res 1996;32: 570-579.
70. Fukumoto Y, Shimokawa H, Ito A, Kadokami T, Yonemitsu Y, Aikawa M, Owada MK, Egashira K, Sueishi K, Nagai R, Yazaki Y, Takeshita A. Inflammatory cytokines cause coronary arteriosclerosis-like changes and alterations in the smooth muscle phenotypes in pigs. J Cardiovasc Pharmacol 1997;29:222-231.
71. Kozai T, Shimokawa H, Yamawaki T, Fukumoto Y, Kadokami T, Kuwata K, Katsumata N, Egashira K, Takeshita A. Platelet activating factor causes hyperconstriction at the inflammatory coronary lesions in pigs in vivo. Coronary Art Dis 1997;8:423-432.
72. Miyata K, Shimokawa H, Yamawaki T, Kunihiro I, Zhou X, Higo T, Tanaka E, Katsumata N, Egashira K, Takeshita A. Endothelial vasodilator function is preserved at the spastic/inflammatory coronary lesions in pigs. Circulation 1999;100: 1432-1437.
73. Shimokawa H, Vanhoutte PM. Hypercholesterolemia causes generalized impairment of endothelium-dependent relaxation to aggregating platelets in porcine coronary arteries. J Am Coll Cardiol 1989;13:1402-1408.
74. Kuga T, Egashira K, Mohri M, Tsutsui H, Harasawa Y, Urabe Y. Bradykinin-induced vasodilation is impaired at the atherosclerotic site but is preserved at the spastic site of human coronary arteries in vivo. Circulation 1995;92:183-189.
75. Yamamoto H, Yoshimura H, Noma M, Kai H, Suzuki S, Tajimi T, Sugihara M, Kikuchi Y. Preservation of endothelium-dependent vasodilation in the spastic segment of the human epicardial coronary artery by substance P. Am Heart J 1992;123:298-303.
76. Okumura K, Yasue H, Ishizaka H, OgawaH, Fujii H, Yoshimura M. Endothelium-dependent dilator response to substance P in patients with coronary spastic angina. J Am Coll Cardiol 1992;20:838-844.
77. Egashira K, Inou T, Yamada A, Hirooka Y, Takeshita A. Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina. J Clin Invest 1992;89:1047-1052.
78. Shimokawa H, Lam JYT, Chesebro JH, Bowie EJW, Vanhoutte PM. Effects of dietary supplementation with cod-liver oil on endothelium-dependent responses in porcine coronary arteries. Circulation 1989;76:898-905.
79. Shimokawa H, Vanhoutte PM. Dietary cod-liver oil improves endotheliumdependent relaxations in hypercholesterolemic and atherosclerotic porcine coronary arteries. Circulation 1989;78:1421-1430.
80. Yamamoto H, Yoshimura H, Noma M, Suzuki S, Kai H, Tajimi T, Sugihara M, Kikuchi Y. Improvement of coronary vasomotion with eicosapentaenoic acid does not inhibit acetylcholine-induced coronary vasospasm in patients with variant angina. Jpn Circ J 1995;59:608-616.
81. Beltrame JF, Sasayama S, Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. J Am Coll Cardiol 1999;33:1442-1452.
82. Yasue H, Omote S, Takizawa A, Nagao M. Coronary arterial spasm in ischemic heart disease and its pathogenesis. A review. Circ Res 1983;52:I147-1152.
83. Shimokawa H, Matsuguchi T, Koiwaya Y, Fukuyama T, Orita Y, Nakamura M. Variable exercise capacity in variant angina and greater exertional thallium-201 myocardial defect during vasospastic ischemic ST segment elevation than with ST depression. Am Heart J 1982;103:142-145.
84. Ozaki Y, Keane D, SerruysPW. Fluctuation of spastic location: a quantitative angiographic study. J Am Coll Cardiol 1995;26:1606-1614.
85. Tashiro H, Shimokawa H, Koyanagi S, Takeshita A. Clinical characteristics of patients with spontaneous remission of variant angina. Jpn Circ J 1993;57:117-122.
86. Takahashi J, Nihei T, Takagi Y, Miyata S, Odaka Y, Tsunoda R, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Momomura S, Yasuda S, Ogawa H, Shimokawa H on behalf of the Japanese Coronary Spasm Association. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina-multicenter registry study of the Japanese Coronary Spasm Association. Eur Heart J (in press).
87. Yokoyama M, Akita H, Hirata K, Usuki S, Fukuzaki H, Itoh H. Supersensitivity of isolated coronary artery to ergonovine in a patient with variant angina. Am J Med 1990; 89:507-515.
88. Satoh S, Tomoike H, Mitsuoka W, Egashira S, Tagawa H, Kuga T, Nakamura M. Smooth muscles from spastic coronary artery segment show hyperreactivity to histamine. Am J Physiol 1990;259:H9-13.
89. Katsumata N, Shimokawa H, Seto M, Kozai T, Yamawaki T, Kuwata K, Egashira K, Ikegaki I, Asano T, Sasaki Y, Takeshita A. Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1b. Circulation 1997;96:4357-4363.
90. Berrige MJ. Inositol triphosphate and calcium signaling. Nature 1993;361:315-325.
91. Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol 2005;25:1767-1775.
92. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994;372:231-236.
93. Hirata K, Kikuchi A, Sasaki T, Kuroda S, Kaibuchi K, Matsuura Y, Seki H, Saida K, Takai Y. Involvement of Rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction. J Biol Chem 1992;267:8719-8722.
94. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-Associated kinase (Rho-kinase). Science 1996;273:245-248.
95. Miwa Y, Hirata K, Matsuda Y, Suematsu M, Kawashima S, Yokoyama M. Augmented receptor-mediated Ca2+ mobilization causes supersensitivity of contractile response to serotonin in atherosclerotic arteries. Circ Res 1994;75:1096-1102.
96. Miyata K, Shimokawa H, Higo T,YamawakiT, Katsumata N, KandabashiT, Tanaka E, Takamura Y, Yogo K, Egashira K, Takeshita A. Sarpogralate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model. J Cardiovasc Pharmacol 2000;35:294-301.
97. Ito A, Shimokawa H, Nakaike R, Fukai T, Sakata M, Takayanagi T, Egashira K, Takeshita A. Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm. Circulation 1994;90:2425-2431.
98. Kadokami T, Shimokawa H, Fukumoto Y, Ito A, Takayanagi T, Egashira K, Takeshita A. Coronary artery spasm does not depend on the intracellular calcium store but is substantially mediated by the protein kinase C-mediated pathway in a swine model with interleukin-1b. Circulation 1996;94:190-196.
99. Kuga T, Shimokawa H, Hirakawa Y, Kadokami Y, Arai Y, Fukumoto Y, Kuwata K, Kozai T, Egashira K, Takeshita A. Increased expression of L-Type calcium channels in vascular smooth muscle cells at spastic site in a porcine model of coronary artery spasm. J Cardiovasc Pharmacol 2000;35:822-828.
100. Kamm KE, Stull JT. Regulation of smooth muscle contractile elements by second messengers. Annu Rev Physiol 1989;51:299-318.
101. ButlerWE, PetersonJW, ZervasNT, Morgan KG. Intracellular calcium, myosin light chain phosphorylation, and contractile force in experimental cerebral vasospasm. Neurosurgery 1996;38:781-788.
102. Seto M, Yano K, Sasaki Y, Azuma H. Intimal hyperplasia enhances myosin phosphorylation in rabbit carotid artery. Exp Mol Pathol 1993;58:1-13.
103. Ikebe M, Hartshorne DJ. Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase. J Biol Chem 1985;260:10027-10031.
104. Seto M, Sasaki Y, Sasaki Y. Stimulus-specific patterns of myosin light chain phosphorylation in smooth muscle of rabbit thoracic artery. Eur J Physiol 1990;415: 484-489.
105. Shimokawa H, Seto M, Katsumata N, Amano M, Kozai T, Yamawaki T, Kuwata K, Kandabashi T, Egashira K, Ikegaki I, Asano T, Kaibuchi K, Takeshita A. Rhokinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999;43:1029-1039.
106. Campbell GR, Campbell JH. Recent advances in molecular pathology: smooth muscle phenotypic changes in arterial wall homeostasis implications for atherosclerosis. Exp Mol Pathol 1985;42:139-162.
107. Seto M, Sakurada K, Kamm KE, Stull JT, Sasaki Y. Myosin light chain diphosphorylation is enhanced by growth promotion of cultured smooth muscle cells. Eur J Physiol 1996;432:7-13.
108. Noda M, Yasuda-Fukazawa C, Moriishi K, Kato T, Okuda T, Kurokawa K, Takuwa Y. Involvement of Rho in GTP-gS-induced enhancement of phosphorylation of 20-kDa myosin light chain vascular smooth muscle cells: inhibition of phosphatase activity. FEBS Lett 1995;367:246-250.
109. Eto M, Ohmori T, Suzuki M, Furuya K, Morita F. A novel protein phosphatase-1 inhibitory protein potentiated by protein kinase C: isolation from porcine aorta media and characterization. J Biochem 1995;118:1104-1107.
110. Kitazawa T, Masuo M, Somlyo AP. G protein-mediated inhibition of myosin lightchain phosphatase in vascular smooth muscle. Proc Natl Acad Sci USA 1991;88: 9307-9310.
111. AmanoM, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K. Phosphorylation and activation of myosin by Rho-Associated kinase (Rho-kinase). J Biol Chem 1996;271:20246-20249.
112. Alessi D, MacDougall LK, Sola MM, Ikebe M, Cohen P. The control of protein phosphatase-1 by targeting subunits. The major myosin phosphatase in avian smooth muscle is a novel form of protein phosphatase-1. Eur J Biochem 1992; 210:1023-1035.
113. Shimizu H, Ito M, Miyahara M, Ichikawa K, Okubo S, Konishi T, Naka M, Tanaka T, Hirano K, Hartshorne DJ. Characterization of the myosin-binding subunit of smooth muscle myosin phosphatase. J Biol Chem 1994;269:30407-30411.
114. Chihara K, Amano M,NakamuraN, YanoT, Shibata M, TokuiT, Ichikawa H, Ikebe R, Ikebe M, Kaibuchi K. Cytoskeletal rearrangements and transcriptional activation of c-fos serum response element by Rho-kinase. J Biol Chem 1997;272:25121-25127.
115. Kureishi Y, Kobayashi S, Amano M, Kimura K, Kanaide H, Nakano T, Kaibuchi K, Ito M. Rho-Associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem 1997;272:12257-122560.
116. Amano M, Chihara K, Nakamura N, Fukata Y, Yano T, Shibata M, Ikebe M, Kaibuchi K. Myosin II activation promotes neurite retraction during the action of Rho and Rho-kinase. Genes Cells 1998;3:177-188.
117. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, Higo T, Egashira K, Takahashi S, Kaibuchi K, Takeshita A. Inhibition of myosin phosphatase by up-regulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1b. Circulation 2000;101:1319-1323.
118. Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-Associated protein kinase in hypertension. Nature 1997;389:990-994.
119. Shimokawa H. Cellular and molecular mechanisms of coronary artery spasm. Lessons from animal models. Jpn Circ J 2000;64:1-12.
120. Masumoto A, MohriM, ShimokawaH, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002;105:1545-1547.
121. Inokuchi K, Ito A, Fukumoto Y, Matoba T, Shiose A, Nishida T, Masuda M, Morita S, Shimokawa H. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J Cardiovasc Pharmacol 2004;44:275-277.
122. Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J Am Coll Cardiol 2003;41:15-19.
123. Shimokawa H, Rashid M. Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci 2007;28:296-302.
124. Satoh K, FukumotoY, Shimokawa H. Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am J Physiol 2011;301:287-296.
125. 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;98:811-817.
126. Satoh K,GodoS, Saito H, Enkhjargal S, ShimokawaH. Dual roles of vascular-derived reactive oxygen species-With a special reference to hydrogen peroxide and cyclophilin A. J Mol Cell Cardiol 2014;73:50-56.
127. Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, Takai Y, Williams CL, Liao JK, Shimokawa H. Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol 2013;33:1591-1600.
128. Shiroto T, Yasuda S, Tsuburaya R, Ito Y, Takahashi J, Ito K, Ishibashi-Ueda H, Shimokawa H. Role of Rho-kinase in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in pigs in vivo. J Am Coll Cardiol 2009; 54:2321-2329.
129. Aizawa K, Yasuda S, Takahashi J, Takii T, Kikuchi Y, Tsuburaya R, Ito Y, Ito K, Nakayama M, Takeda M, Shimokawa H. Involvement of Rho-kinase activation in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in patients with coronary artery disease. Circ J 2012;76:2552-2560.
130. Tsuburaya R, Yasuda S, Shiroto T, Ito Y, Gao JY, Aizawa K, Kikuchi Y, Ito K, Takahashi J, Ishibashi-Ueda H, Shimokawa H. Long-Term treatment with nifedipine suppresses coronary hyperconstricting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo: possible involvement of Rhokinase pathway. Eur Heart J 2012;33:791-799.
131. Kikuchi Y, Yasuda S, Aizawa K, Tsuburaya R, Ito Y, Takeda M, Nakayama M, Ito K, Takahashi J, Shimokawa H. Enhanced Rho-kinase activity in circulating neutrophils of patients with vasospastic angina: a possible biomarker for diagnosis and disease activity assessment. J Am Coll Cardiol 2011;58:1231-1237.
132. Nihei T, Takahashi J, Tsuburaya R, Ito Y, Shiroto T, Hao K, Takagi Y, Matsumoto Y, Nakayama M, Miyata S, Sakata Y, Ito K, Shimokawa H. Circadian variation of Rhokinase activity in circulating leukocytes of patients with vasospastic angina. Circ J 2014;78:1183-1890.
133. Doe Z, Fukumoto Y, Takaki A, Tawara S, Ohashi J, Nakano M, Tada T, Saji K, Sugimura K, Fujita H, Hoshikawa Y, Nawata J, Kondo T, Shimokawa H. Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension. Circ J 2009;73:1731-1739.
134. Doe Z, Fukumoto Y, Sugimura K, Miura Y, Tatebe S, Yamamoto S, Aoki T, Nochioka K, Nergui S, Yaoita N, Satoh K, Kondo M, Nakano M, Wakayama Y, Fukuda K, Nihei T, Kikuchi Y, Takahashi J, Shimokawa H. Rho-kinase activation in patients with heart failure. Circ J 2013;77:2542-2450.
135. Kajikawa M,NomaK, MaruhashiT, Mikami S, IwamotoY, Iwamoto A, MatsumotoT, Hidaka T, Kihara Y, Chayama K, Nakashima A, Goto C, Liao JK, Higashi Y. Rho-Associated kinase activity is a predictor of cardiovascular outcomes. Hypertension 2014;63:856-864.
136. Takagi Y, Yasuda S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H. Japanese Coronary Spasm Association. Clinical characteristics and long-Term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association. Circ Arrhythm Electrophysiol 2011;4:295-302.
137. Takagi Y, Yasuda S, Takahashi J, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H. Japanese Coronary Spasm Association. Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association. Eur Heart J 2013;34:258-267.
138. Kawana A, Takahashi J, Takagi Y, Yasuda S, Sakata Y, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Kubo N, Momomura S, Ogawa H, Shimokawa H. Japanese Coronary Spasm Association. Gender differences in the clinical characteristics and outcomes of patients with vasospastic angina-A report from the Japanese Coronary Spasm Association-. Circ J 2013;77: 1267-1274.
139. Takagi Y, Takahashi J, Yasuda S, Miyata S, Tsunoda R, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H. Japanese Coronary Spasm Association. Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association. J Am Coll Cardiol 2013; 62:1144-1153.
140. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, SechtemU. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (AbnormalCOronaryVAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol 2012;59:655-662.
141. Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, Hill S, Schaufele T, Mahrholdt H, Kaski JC, Sechtem U. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation 2014;129:1723-1730.