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診療・研究内容

(8)血管生物学(動脈硬化/基礎)

我々の研究グループでは、近年生体内における様々な生理機能の調節に関わる分子として、また創薬ターゲットとして注目されているRho-kinaseに関する基礎研究を行っています。

Rho-kinaseとは?

Rho-kinaseは、1990年代半ばのほぼ同時期に2つの日本の研究グループと1つのシンガポールの研究グループから同定された低分子量Gタンパク質Rhoの下流に存在するセリン・スレオニンリン酸化酵素です。Rho-kinaseは生体内に広く発現しており、様々なアゴニスト刺激による細胞内情報伝達経路に介在することで、平滑筋細胞の収縮弛緩、アクチン骨格の再構成や細胞接着、遊走、増殖、遺伝子発現など多岐にわたる細胞の機能に関与しています(図1)。その中でも今日まで最も研究されている機能としては血管平滑筋の収縮弛緩への関与です。

図1
Rho-kinaseが関与する生理機能(血管平滑筋の収縮弛緩)

血管平滑筋の収縮弛緩は、ミオシン軽鎖キナーゼ(MLCK)活性とミオシン軽鎖フォスファターゼ(MLCPh)活性のバランスにより決定されるミオシン軽鎖(MLC)のリン酸化が中心的役割を果たしています。これを制御する因子として、古くから細胞内Ca2+濃度の変化が広く知られています。一方、Rho-kinaseは細胞内Ca2+濃度非依存的に血管平滑筋の収縮弛緩を制御しています。すなわち、収縮性血管作動物質の刺激により、G蛋白に共役した受容体を介して低分子量G蛋白質であるRhoが活性化され、その標的タンパクの一つであるRho-kinaseが活性化されます。活性化されたRho-kinaseは、MLCPhのミオシン結合サブユニット(MBS)をリン酸化することによりその活性を阻害します。その結果、MLCK/MLCPh活性のバランスが崩れ、MLCのリン酸化が上昇することで血管平滑筋は収縮します(図2)。

図2
循環器疾患とRho-kinase阻害薬

我々はこれまでに動脈硬化性疾患のみならず、冠動脈攣縮や高血圧、肺高血圧、虚血−再灌流など、多岐にわたる循環器疾患においてRho-kinaseがその病態に深く関与しており、Rho-kinase阻害薬がそれらの治療に有効である可能性を見出してきました(図3)。図3

また、循環器疾患以外の疾患においてもRho-kinaseの病態への関与が数多く報告されており、近年その阻害薬の開発には注目が集まっています。現在臨床の現場で使用できるRho-kinase阻害薬は静注薬が脳血管攣縮抑制の保険適応を持つファスジルのみでありますが、国内外で約15社が選択的Rho-kinase阻害薬の開発を進めており、その多くが心血管病の適応を目指しています。以下、我々が行ってきた基礎研究の結果を一部紹介します。

ブタ動脈硬化モデルにおける検討

我々は、ブタの大腿動脈バルーン傷害モデルにおける新生内膜肥厚が、dominant-negative Rho-kinaseを発現させることにより抑制されることを見出しました。また、ブタ冠動脈外膜に酸化LDL とMCP-1を同時に慢性投与すると、同部におけるマクロファージの内膜および中膜への遊走と新生内膜肥厚が生じ、これらの病的反応がRho-kinase阻害薬であるファスジルの慢性投与により抑制されることも確認しました(図4)。さらに、ブタ冠動脈ステント留置後の再狭窄に対しても、ファスジルの慢性経口投与によりその形成が抑制されました。特筆すべきことに、IL-1誘発モデルにおいては、いったん形成された動脈硬化病変に対しても、ファスジル慢性投与により病変が退縮しました。これらの全ての動脈硬化モデルの病変部でRho-kinase活性が亢進していました。以上の結果から、Rho-kinaseを抑制することが動脈硬化、さらには心筋梗塞や不安定狭心症などの急性冠症候群に対する新たな治療標的となりうることが示唆されます。図4

冠動脈攣縮モデルにおける検討

我々は、独自に開発した冠動脈攣縮モデル(ブタ)に対し、冠動脈攣縮部位にRho-kinase特異的な抑制作用を有するヒドロキシファスジルまたはY-27632を前投与したところ、in vivoにおけるセロトニン誘発性冠動脈攣縮が用量依存性に抑制されることを見出しました(図5)。摘出血管を用いたin vitroにおけるセロトニン誘発性の冠動脈過収縮とMLCリン酸化亢進もまた用量依存性に抑制されました。また、冠動脈攣縮部位ではRho-kinaseのmRNA発現が増加しており、セロトニンに対する収縮時にのみRho-kinase活性が亢進し、この亢進はY-27632の前投与により有意に抑制されることも明らかにしました。これらの事実は、動物モデルにおける冠動脈攣縮反応は攣縮部血管平滑筋のRho-kinaseを介するシグナル伝達経路が亢進しており、その結果としてMLCPh活性が抑制されてCa2+感受性が増強し、過収縮を生じている可能性を示唆しています。図5

現在我々は、当科循環グループと共同で肺高血圧症に対するRho-kinase阻害薬ファスジルの基礎および臨床研究を進めています。最近の基礎研究の成果として、ファスジルは肺高血圧症モデル動物に対して極めて高い治療効果を示すことを明らかにしました。また、臨床研究においては、肺高血圧症患者におけるファスジルの急性効果を検討したところ、患者の上昇している肺血管抵抗を低下させる作用を有することを見出しました。今後も引き続き基礎および臨床において、肺高血圧症におけるRho-kinaseの役割およびファスジルの効果について明らかにすることを目指します。

 

動脈硬化/肺高血圧症他

我々はこれまで動脈硬化と炎症に関する基礎研究を行ってきており(Circulation 1997・2001, JACC 2003など)、動脈硬化症に対する治療戦略としては、量的改善のみならず質的改善が重要であると考えている。その質的改善には血管内皮機能の改善および粥状動脈硬化症におけるプラークの安定化が重要であり、抗炎症・マクロファージの活性化抑制・コラーゲン代謝の改善が重要な役割を果たすことを明らかにし(Circulation 2001・2004)、血管攣縮などの血管機能低下にはRhoキナーゼ経路が関与していることを明らかにしてきた(ATVB 2004, J Cardivasc Pharmacol 2004・2007など)。さらに最近、重症虚血における血管新生にエリスロポイエチン受容体経路が重要であることも示した(Circ Res 2007)。また独自のin vitroの系を用い、pulse pressure, stretch, shear stressなどの機械的刺激による血管平滑筋細胞機能を検討している。さらに肺高血圧症における肺動脈病変の進行にRhoキナーゼ経路やエリスロポイエチン系が重要であることも示してきた(Circ Res 2004, Circulation 2006, J Cardiovasc Pharmacol 2006・2007など)。

動脈硬化/肺高血圧症他

 

主な研究業績(2000年以降)
2017年
  1. Kina-Tanada M, Sakanashi M, Tanimoto A, Kaname T, Matsuzaki T, Noguchi K, Uchida T, Nakasone J, Kozuka C, Ishida M, Kubota H, Taira Y, Totsuka Y, Kina S, Sunakawa H, Omura J, Satoh K, Shimokawa H, Yanagihara N, Maeda S, Ohya Y, Matsushita M, Matsuki H, Arasaki A, Tsutsui M. Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice. Diabetologia. 60:1138-1151,2017.PDF
  2. Satoh T, Satoh K, Yaoita N, Kikuchi N, Omura J, Kurosawa R, Numano K, Elias-Al-Mamun M, AbdulHai Siddique MAH, Sunamura S, Nogi M, Suzuki K, Miyata S, John Morser J, Shimokawa H. Activated TAFI promotes the development of chronic thromboembolic pulmonary hypertension - A possible novel therapeutic target - Circ Res. 120:1246-1262,2017.PDF
  3. Satoh K, Sugimura K, Shimokawa H. Rho-kinase as a therapeutic target for pulmonary hypertension. In: Fukumoto Y (ed), Diagnosis and Treatment of Pulmonary Hypertension. From Bench to Bedside, pp. 67-76. Springer Nature, Singapore, 2017.
  4. Ventura-Clapier R, Dworatzek E, Seeland U, Kararigas G, Arnal JF Brunelleschi S, Carpenter T, Erdmann J, Franconi F, Giannetta E, Glezerman M, Hofmann S, Junien C, Katai M, Kublickiene K, Konig IR, Majdic G, Malorni W, Mieth C, Miller V, Reynolds R, Shimokawa H, Tannenbaum C, D`Ursi AM, Regitz-Zagrosek V. Sex in basic research -Concepts in the cardiovascular field- Cardiovasc Res. 113:711-724,2017.PDF
  5. Godo S, Shimokawa H. Divergent roles of endothelial nitric oxide synthases system in maintaining cardiovascular homeostasis. Free Radical Biology & Medicine. DOI:10.1016/j.freeradbiomed.2016.12.019PDF
2016年
  1. Godo S, Sawada A, Saito H, Ikeda S, Enkhjargal B, Suzuki K, Tanaka S, Shimokawa H. Disruption of physiological balance between nitric oxide and endothelium-dependent hyperpolarization impairs cardiovascular homeostasis in mice. Arterioscler Thromb Vasc Biol. 36:97-107,2016.PDF
  2. Hatanaka K, Ito K, Shindo T, Kagaya Y, Ogata T, Eguchi K, Kurosawa R, Shimokawa H. Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: Roles of mechanotransduction. Am J Physiol. 311:C378-385,2016.PubMed
  3. Jiang L, Konishi H, Nurwidya F, Satoh K, Takahashi F, Ebinuma H, Fujimura K, Takasu K, Jiang M, Shimokawa H, Bujo H, Daida H. Deletion of LR11 attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation with medial thickening in mice. Arterioscler Thromb Vasc Biol. 36:1972-1979,2016.PDF
  4. Kudo S, Satoh K, Nogi M, Suzuki K, Sunamura S, Omura J, Kikuchi N, Kurosawa R, Satoh T, Minami T, Ikeda S, Shimokawa H. SmgGDS as a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy and fibrosis. -Novel mechanism of the pleiotropic effects of statins- Hypertension. 67:878-889,2016.PDF
  5. Minami T, Satoh K, Nogi M, Kudo S, Miyata S, Tanaka S, Shimokawa H. Statins up-regulate SmgGDS through ß1-integrin/Akt1 pathway in endothelial cells. Cardiovasc Res. 109:151-161,2016.PDF
  6. Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Otsuki T, Kozu K, Numano K, Suzuki K, Sunamura S, Tatebe S, Aoki T, Sugimura K, Miyata S, Hoshikawa Y, Okada Y, Shimokawa H. Protective roles of endothelial AMP-activated protein kinase against hypoxia-induced pulmonary hypertension in mice. Circ Res. 119:197-209,2016.PDF
  7. Shimokawa H, Godo S. Diverse functions of endothelial NO synthases system: NO and EDH. J Cardiovasc Pharmacol. 67:361-366,2016.PDF
  8. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-kinase in the cardiovascular system. Circ Res. 118:352-366,2016.PDF
  9. Suzuki K, Satoh K, Ikeda S, Sunamura S, Otsuki T, Satoh T, Kikuchi N, Omura J, Kurosawa R, Nogi M, Numano K, Sugimura K, Aoki T, Tatebe S, Miyata S, Mukherjee R, Spinale FG, Kadomatsu K, Shimokawa H. Basigin promotes cardiac fibrosis and failure in response to chronic pressure-overload in mice. Arterioscler Thromb Vasc Biol. 36:636-646,2016.PDF
  10. Yaoita N, Satoh K, Shimokawa H. Novel therapeutic targets of pulmonary hypertension. (Review) Arteriosclr Thromb Vasc Biol. 2016;36:e97-e102. DOI: 10.1161/ATVBAHA.116.308263.PDF
  11. Yaoita N, Satoh K, Satoh T, Sugimura K, Tatebe S, Yamamoto S, Aoki T, Miura M, Kawamura T, Horiuchi H, Fukumoto Y, Shimokawa H. Thrombin-activatable fibrinolysis inhibitor in chronic thromboembolic pulmonary hypertension. Arterioscler Throm Vasc Biol. 36:1220-1229,2016.PubMed
2015年
  1. Noda K, Godo S, Saito H, Tsutsui M, Shimokawa H. Opposing roles of nitric oxide and Rho-kinase in lipid metabolism in mice.Tohoku J Exp Med. 235:171-183,2015.PDF
  2. Satoh K, Kikuchi N, Kurosawa R, Shimokawa H. PDE1C negatively regulates growth factor receptor degradation and promotes VSMC proliferation. Circ Res. 116:1098-1100,2015.PubMed
  3. Satoh K. Cyclophilin A in cardiovascular homeostasis and diseases. Tohoku J Exp Med. 235:1-15,2015.PDF
  4. Shimokawa H, Satoh K. 2015 ATVB Plenary lecture: Translational research on Rho-kinase in cardiovascular medicine. Arterioscler Thromb Vasc Biol. 35:1756-1769,2015.PDF
  5. Shimokawa H, Satoh K. Light and dark of reactive oxygen species for vascular function. J Cardiovasc Pharmacol. 65:412-418,2015.PubMed
  6. Tsutsui M, Tanimoto A, Tamura M, Mukae H, Yanagihara N, Shimokawa H, Otsuji Y. Significance of nitric oxide synthases: Lessons from triple nitric oxide synthases null mice. J Pharmacol Sci. 127:42-52,2015.PDF
2014年
  1. Abe Y, Ito K, Hao K, Shindo T, Ogata T, Kagaya Y, Kurosawa R, Nishimiya K, Satoh K, Miyata S, Kawakami K, Shimokawa H. Extracorporeal low-energy shock-wave therapy exerts anti-inflammatory effects in a rat model of acute myocardial infarction. Circ J. 78:2915-2925,2014.PDF
  2. Al-Mamun ME, Satoh K, Tanaka S, Shimizu T, Nergui S, Miyata S, Fukumoto Y, Shimokawa H. Combination therapy with fasudil and sildenafil ameliorates monocrotaline-induced pulmonary hypertension and survival in rats. Circ J. 78:967-976,2014.PDF
  3. 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. 34:1505-1513,2014.PDF
  4. Ikeda S, Satoh K, Kikuchi N, Miyata S, Suzuki K, Omura J, Shimizu T, Kobayashi K, Kobayashi K, Fukumoto Y, Sakata Y, Shimokawa H. Crucial role of Rho-kinase in pressure-overload-induced right ventricular hypertrophy and dysfunction in mice. Arterioscler Thromb Vasc Biol. 34:1260-1271,2014.PDF
  5. Nergui S, Fukumoto Y, Do.e Z, Nakajima S, Shimizu T, Ikeda S, Elias-Al-Mamun M, Shimokawa H. Role of eNOS and collagen metabolism in right ventricular remodeling due to pulmonary hypertension. Circ J. 78:1465-1474,2014.PDF
  6. Noda K, Nakajima S, Godo S, Saito H, Ikeda S, Shimizu T, Enkhjargal B, Fukumoto Y, Tsukita S, Yamada T, Katagiri H, Shimokawa H. Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice. PLoS One. 2014;9(11):e110446.PDF
  7. Noguchi S, Yatera K, Wang KY, Oda K, Akata K, Yamasaki K, Kawanami T, Ishimoto H, Toyohira Y, Shimokawa H, Yanagihara N, Tsutsui M, Mukae H. Nitric oxide exerts protective effects against bleomycin-induced pulmonary fibrosis in mice. Respir Res. 15:92.doi:10.1186/s12931-014-0092-3.PDF
  8. Satoh K, Godo S, Saito H, Enkhjargal S, Shimokawa H. Dual roles of vascular-derived reactive oxygen species -With a special reference to hydrogen peroxide and cyclophilin A- J Mol Cell Cardiol. 73:50-56,2014.PDF
  9. Satoh K, Satoh T, Kikuchi N, Omura J, Kurosawa R, Suzuki K, Sugimura K, Aoki T, Nochioka K, Tatebe S, Yamamoto S, Miura M, Shimizu T, Ikeda S, Yaoita N, Fukumoto Y, Minami T, Miyata S, Nakamura K, Ito H, Kadomatsu K, Shimokawa H. Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circ Res. 115:738-750,2014.PDF
  10. Shimokawa H. 2014 William Harvey Lecture. Importance of coronary vasomotion abnormalities -From bench to bedside- Eur Heart J. 35:3180-3193,2014.PDF
  11. Shimokawa H, Satoh K. Recent Highlights of ATVB: Vascular function. Arteriosclr Thromb Vasc Biol. 34:2359-2362,2014.
  12. Shiroto T, Romero N, Sugiyama T, Sartoretto JL, Kalwa H, Yan Z, Shimokawa H, Michel T. Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium. PLoS One 2014;9(2):e87871.PDF
  13. Tsutsui M, Shimokawa H, Tanimoto A, Yanagihara N, Otsuji Y. Roles of nitric oxide synthases in arteriosclerotic vascular disease-Insights from murine genetic models- J Clin Exp Cardiol. 5: 318. doi:10.4172/2155-9880.1000318,2014.PDF
  14. Uchida T, Furuno Y, Tanimoto A, Toyohira Y, Arakaki K, Kina-Tanada M, Kubota H, Sakanashi M, Matsuzaki T, Noguchi K, Nakasone J, Igarashi T, Ueno S, Matsushita M, Ishiuchi S, Masuzaki H, Ohya Y, Yanagihara N, Shimokawa H, Otsuji Y, Tamura M, Tsutsui M. Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse. J Mol Cell Cardiol. 77:29-41,2014.PDF
  15. Yamaya S, Ozawa H, Kanno H, Kishimoto KN, Sekiguchi A, Tateda S, Yahata K, Ito K, Shimokawa H, Itoi E. Low-energy extracorporeal shock wave therapy promotes VEGF expression and neuroprotection and improves locomotor recovery after spinal cord injury. J Neurosurg. 121:1514-1525,2014.PDF
  16. Yaoita N, Shirakawa R, Fukumoto Y, Sugimura K, Miyata S, Miura Y, Nochioka K, Miura M, Tatebe S, Aoki T, Yamamoto S, Satoh K, Kimura T, Shimokawa H, Horiuchi H. Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension (CTEPH). Arterioscler Thromb Vasc Biol. 34:2486-2494,2014.PDF
2013年
  1. Eba S, Hoshikawa Y, Moriguchi T, Mitsuishi Y, Satoh H, Ishida K, Watanabe T, Shimizu T, Shimokawa H, Okada Y, Yamamoto M, Kondo T. The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice. Am J Respir Cell Mol Biol. 49:324-333,2013.PDF
  2. Obukuro K, Nobunaga M, Takigawa M, Morioka H, Hisatsune A, Isohama Y, Shimokawa H, Tsutsui M, Katsuki H. Nitric Oxide Mediates Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide Isomerase. J Neurosci. 33:12557-12568,2013.PDF
  3. Satoh K, Fukumoto Y, Sugimura K, Miura Y, Aoki T, Nochioka K, Tatebe S, Miyamichi-Yamamoto S, Shimizu T, Osaki S, Takagi Y, Tsuburaya R, Ito Y, Matsumoto Y, Nakayama M, Takeda M, Takahashi J, Ito K, Yasuda S, Shimokawa H. Plasma cyclophilin A is a novel biomarker for coronary artery disease. Circ J. 77:447-455,2013.PDF
  4. Shibata K, Shimokawa H, Yanagisawa N, Otsuji Y, Tsutsui M. Nitric oxide synthases and heart failure -Lessons from genetically manipulated mice- J UOEH. 35:147-158,2013.PDF
  5. Shimizu T, Fukumoto Y, Tanaka S, 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. 33:2780-2791,2013.PDF
  6. Takahashi K, Matsumoto Y, Do.e Z, Kanazawa M, Satoh K, Shimizu T, Sato A, Fukumoto Y, Shimokawa H. Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation. PLoS One 2013;8(8):e72558.PDF
  7. 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. 33:1591-1600,2013.PDF
2012年
  1. 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. 76:2552-2560,2012.PDF
  2. Benkhoff S, Loot AE, Pierson I, Sturza A, Kohlstedt K, Fleming I, Shimokawa H, Grisk O, Brandes RP, Schroder K. Leptin potentiates endothelium-dependent relaxation by inducing endothelial expression of neuronal NO synthase. Arteriscler, Thromb, Vasc Biol. 32:1605-1612,2012.PDF
  3. Hayashi D, Kawakami K, Ito K, Ishii K, Tanno H, Imai Y, Kanno E, Maruyama R, Shimokawa H, Tachi M. Low-energy extracorporeal shock wave therapy enhances skin wound healing in diabetic mice: a critical role of endothelial nitric oxide synthase. Wound Repair Regen. 20:887-895,2012.PDF
  4. Kromhout D, Yasuda S, Geleijnse JM, Shimokawa H. Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work? Eur Heart J. 33:436-443,2012.PDF
  5. Nakajima S, Ohashi J, Sawada A, Noda K, Fukumoto Y, Shimokawa H. Essential role of bone marrow for microvascular endothelial and metabolic functions in mice. Circ Res. 111:87-96,2012.PDF
  6. Noda K, Hosoya M, Nakajima S, Ohashi J, Fukumoto Y, Shimokawa H. Anti-atherogenic effects of the combination therapy with olmesartan and azelnidipine in diabetic apolipoprotein e-deficient mice. Tohoku J Exp Med. 228:305-315,2012.PDF
  7. Ohashi J, Sawada A, Nakajima S, Noda K, Takaki A, Shimokawa H. Mechanisms for enhanced endothelium-derived hyperpolarizing factor-mediatedresponses in microvessels in mice. Circ J. 76:1768-1779,2012.PDF
  8. Satoh K, Fukumoto Y, Nakano M, Kagaya Y, Shimokawa H. Emergence of the erythropoietin/erythropoietin receptor system as a novel cardiovascular therapeutic target. J Cardiovasc Pharmacol. 58:570-574,2012.PubMed
  9. Satoh S, Kawasaki K, Ikegaki I, Asano T, Shimokawa H. Evidence of a direct cellular protective effect of Rho-kinase inhibitors on endothelin-induced cardiac myocyte hypertrophy. Biochem Biophys Res Commun. 424:338-340,2012.PDF
  10. 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 Rho-kinase pathway. Eur Heart J. 33:791-799,2012.PDF
2011年
  1. Fukumoto Y, Shimokawa H. Recent progress in the management of pulmonary hypertension. Circ J. 75:1801-1810,2011. (Review)PubMed
  2. Furuno Y, Morishita T, Toyohira Y, Yamada S, Ueno S, Morisada N, Sugita K, Noguchi K, Sakanashi M, Miyata H, Tanimoto A, Sasaguri Y, Shimokawa H, Otsuji Y, Yanagihara N, Tamura M, Tsutsui M. Crucial vasculoprotective role of the whole nitric oxide synthase system in vascular lesion formation in mice: Involvement of bone marrow-derived cells. Nitric Oxide. 25:350-359,2011.PDF
  3. Nigro P, Satoh K, O'Dell MR, Soe NN, Cui Z, Mohan A, Abe J, Alexis J, Sparks JD, Berk BC. Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice. J Exp Med. 208:53-66,2011.PubMed
  4. Rabieyousefi M, Soroosh P, Satoh K, Date1 F, Ishii N, Yamashita M, Oka M, McMurtry IF, Shimokawa H, Nose M, Sugamura K, Ono M. Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension. BMC Immunology. 12:67-79,2011.PDF
  5. Satoh K, Berk BC, Shimokawa H. Vascular-derived reactive oxygen species for homeostasis and diseases. Nitric Oxide. 25:211-215,2011. (Review)PubMed
  6. Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am J Physiol. 301:287-296,2011.PDF
  7. Satoh K, Nigro P, Zeidan A, Soe NN, Jaffré F, Oikawa M, O'Dell MR, Cui Z, Menon P, Lu Y, Mohan A, Yan C, Blaxall BC, Berk BC. Cyclophilin A promotes cardiac hypertrophy in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol. 31:1116-1123,2011.PubMed
2010年
  1. Nakano M, Fukumoto Y, Satoh K, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H. OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization. Cardiovasc Res. 79:212-220,2010.PubMed
  2. Nigro P, Abe JI, Woo CH, Satoh K, McClain C, O'Dell MR, Fujiwara K, and Berk BC. PKCζ decreases eNOS protein stability via inhibitory phosphorylation of ERK5. Blood. 116:1971-1979,2010.PubMed
  3. Satoh K, Nigro P, Berk BC. Oxidative stress and vascular smooth muscle cell growth: A mechanistic linkage by cyclophilin A. Antioxidants & Redox Signaling. 12:675-682,2010.PubMed
  4. Satoh K, Shimokawa H, Berk BC. Cyclophilin A: promising new target in cardiovascular therapy. Circulation J. 74:2249-2256,2010. (review)PubMed
  5. Sugimura K, Fukumoto Y, Nawata J, Wang H, Onoue N, Tada T, Shirato K, Shimokawa H. Hypertension promotes phosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 in rats -Implication for the pathogenesis of hypertensive vascular disease-. Tohoku J Exp Med. 222:201-210,2010.PubMed
  6. Tatebe S, Fukumoto Y, Sugimura K, Nakano M, Miyamichi S, Satoh K, Oikawa M, Shimokawa H. Optical coherence tomography as a novel diagnostic tool for distal type chronic thromboembolic pulmonary hypertension. Circ J. 74(8):1742-1744,2010Aug.PubMed
2009年
  1. Rashid M, Tawara S, Fukumoto Y, Seto M, Yano K, Shimokawa H. Importance of rac1 signaling pathway inhibition in the pleiotropic effects of HMG-CoA reductase inhibitors. Circ J. 73:361-370,2009.PubMed
  2. Satoh K, Fukumoto Y, Nakano M, Ishii N, Sugamura K, Shimokawa H. Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovac Res. 81:226-234,2009.PubMed
  3. Satoh K, Nigro P, Matoba T, O'Dell MR, Cui Z, Shi X, Mohan A, Yan C, Abe J, Illig KA, Berk BC. Cyclophilin a enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med. 15:649-656,2009.PubMed
2008年
  1. Fukui S, Fukumoto Y, Suzuki J, Saji K, Nawata J, Tawara S, Shinozaki T, Kagaya Y, Shimokawa H. Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats. J Cardiovasc Pharmacol. 51:317-326,2008.PubMed
  2. Oi K, Fukumoto Y, Ito K, Uwatoku T, Abe K, Hizume T, Shimokawa H. Extracorporeal shock wave therapy ameliorates hindlimb ischemia in rabbits. Tohoku J Exp Med. 214:151-158,2008.PubMed
  3. Onoue N, Nawata J, Tada T, Zhulanqiqige D, Wang H, Sugimura K, Fukumoto Y, Shirato K, Shimokawa H. Increased static pressure promotes migration of vascular smooth muscle cells: Involvement of the Rho-kinase pathway. J Cardiovasc Pharmacol. 51:55-61,2008.PubMed
  4. Satoh K, Berk BC. Circulating smooth muscle progenitor cells: novel players in plaque stability. Cardiovasc Res. 77:445-447,2008.PubMed
  5. Satoh K, Matoba T, Suzuki J, O'Dell MR, Nigro P, Berk BC. Cyclophilin A mediates vascular remodeling by promoting inflammation and Vascular Smooth Muscle Cell proliferation. Circulation. 117:3088-3098,2008.PubMed
  6. Ulrich M, Petre A, Youhnovski N, Promm F, Schirle M, Schumm M, Pero RS, Doyle A, Checkel J, Kita H, Thiyagarajan N, Acharya KR, Schmid-Grendelmeier PS, Simon HU, Schwart H, Tsutsui M, Shimokawa H, Bellon G, Lee J, Przybyski M, Doring G. Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase. J Biol Chem. 283:28629-28640,2008.PDF
2007年
  1. Fukumoto Y, Mohri M, Inokuchi K, Ito A, Hirakawa Y, Masumoto A, Hirooka Y, Takeshita A, Shimokawa H. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. J Cardiovasc Pharmacol. 49:117-121,2007.PubMed
  2. Fukumoto Y, Tawara S, Shimokawa H. Recent progress in the treatment of pulmonary arterial hypertension: expectation for rho-kinase inhibitors. Tohoku J Exp Med. 211:309-320,2007.PubMed
  3. Jiang BH, Tawara S, Abe K, Takaki A, Fukumoto Y, Shimokawa H. Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol. 49:85-89,2007.PubMed
  4. Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, Sugamura K, Shimokawa H. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res. 100:662-669,2007.PubMed
  5. Saji K, Fukumoto Y, Suzuki J, Fukui S, Nawata J, Shimokawa H. Colchicine, a microtubule depolymerizing agent, inhibits myocardial apoptosis in rats. Tohoku J Exp Med. 213:139-148,2007.PubMed
  6. Shimokawa H, Rashid M. Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci. 28:296-302,2007.PubMed
  7. Tawara S, Fukumoto Y, Shimokawa H. Effects of combined therapy with a Rho-Kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol. 50:195-200,2007.PubMed
2006年
  1. Abe K, Tawara S, Oi K, Hizume T, Uwatoku T, Fukumoto Y, Kaibuchi K, Shimokawa H. Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol. 48:280-285,2006.PubMed
  2. Hizume T, Morikawa K, Takaki A, Abe K, Sunagawa K, Amano M, Kaibuchi K, Kubo C, Shimokawa H. Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm. Circ Res. 99:767-775,2006.PubMed
  3. Satoh K, Kagaya Y, Nakano M, Ito Y, Ohta J, Tada H, Karibe A, Minegishi N, Suzuki N, Yamamoto M, Ono M, Watanabe J, Shirato K,Ishii N, Sugamura K, Shimokawa H. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation. 113:1442-1450,2006.PubMed
2005年
  1. Abe K, Morikawa K, Hizume T, Uwatoku T, Oi K, Seto M, Ikegaki I, Asano T, Kaibuchi K, Shimokawa H. Prostacyclin does not inhibit rho-kinase: an implication for the treatment of pulmonary hypertension. J Cardiovasc Pharmacol. 45:120-124,2005.PubMed
  2. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 91:391-392,2005.PubMed
  3. Hiroki J, Shimokawa H, Mukai Y, Ichiki T, Takeshita A. Divergent effects of estrogen and nicotine on Rho-kinase expression in human coronary vascular smooth muscle cells. Biochem Biophys Res Commun. 326:154-159,2005.PubMed
  4. Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target in cardiovascular medicine. Arterioscler Thromb Vasc Biol. 25:1767-1775,2005.PubMed
  5. Yada T, Shimokawa H, Hiramatsu O, Kajita T, Shigeto F, Tanaka E, Shinozaki Y, Mori H, Kiyooka T, Katsura M, Ohkuma S, Goto M, Ogasawara Y, Kajiya F. Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo. J Am Coll Cardiol. 45:599-607,2005.PubMed
2004年
  1. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshit A. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 94:385-393,2004.PubMed
  2. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Kaibuchi K, Takeshita A. Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice. Circ Res. 94:46-52,2004.PubMed
  3. Hattori T, Shimokawa H, Higashi M, Hiroki J, Mukai Y, Tsutsui H, Kaibuchi K, Takeshita A. Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice. Circulation. 109:2234-2239,2004.PubMed
  4. Hiroki J, Fukumoto Y, Shimokawa H, Hirooka Y, Takeshita A. Inhibition of Rho-kinase by fasudil preventing anginal attacks associated with spastic angina: a case report. J Cardiol. 44:161-164,2004.PubMed
  5. Hiroki J, Shimokawa H, Higashi M, Morikawa K, Kandabashi T, Kawamura N, Kubota T, Ichiki T, Amano M, Kaibuchi K, Takeshita A. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol. 37:537-546,2004.PubMed
  6. 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. J Cardiovasc Pharmacol. 44:275-277,2004.PubMed
  7. Matsumoto Y, Uwatoku T, Oi K, Abe K, Hattori T, Morishige K, Eto Y, Fukumoto Y, Nakamura K, Shibata Y, Matsuda T, Takeshita A, Shimokawa H. Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: involvement of multiple mechanisms. Arterioscler Thromb Vasc Biol. 24:181-186,2004.PubMed
  8. Oi K, Shimokawa H, Hiroki J, Uwatoku T, Abe K, Matsumoto Y, Nakajima Y, Nakajima K, Takeichi S, Takeshita A. Remnant lipoproteins from patients with sudden cardiac death enhance coronary vasospastic activity through upregulation of Rho-kinase. Arterioscler Thromb Vasc Biol. 24:918-922,2004.PubMed
  9. Shiotani S, Shimada M, Suehiro T, Soejima Y, Yosizumi T, Shimokawa H, Maehara Y. Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats. Transplantation. 78:375-382,2004.PubMed
2003年
  1. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res. 93:767-775,2003.PubMed
  2. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Eto Y, Morishige K, Matsumoto Y, Obara K, Nakayama K, Takahashi S, Takeshita A. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol. 23:2209-2214,2003.PubMed
  3. 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. 41:15-19,2003.PubMed
2002年
  1. Kandabashi T, Shimokawa H, Mukai Y, Matoba T, Kunihiro I, Morikawa K, Ito M, Takahashi S, Kaibuchi K, Takeshita A. Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries. Arterioscler Thromb Vasc Biol. 22:243-248,2002.PubMed
  2. Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 105:1545-1547,2002.PubMed
  3. Satoh S, Ikegaki I, Toshima Y, Watanabe A, Asano T, Shimokawa H. Effects of Rho-kinase inhibitor on vasopressin-induced chronic myocardial damage in rats. Life Sci. 72:103-112,2002.PubMed
  4. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, Nakashima M, Kato K. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol. 40:751-761,2002.PubMed
  5. Shimokawa H. Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Pharmacol. 39:319-327,2002.PubMed
2001年
  1. Ikegaki I, Hattori T, Yamaguchi T, Sasaki Y, Satoh SI, Asano T, Shimokawa H. Involvement of Rho-kinase in vascular remodeling caused by long-term inhibition of nitric oxide synthesis in rats. Eur J Pharmacol. 427:69-75,2001.PubMed
  2. Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension. 38:1307-1310,2001.PubMed
  3. Morishige K, Shimokawa H, Eto Y, Hoshijima M, Kaibuchi K, Takeshita A. In vivo gene transfer of dominant-negative rho-kinase induces regression of coronary arteriosclerosis in pigs. Ann N Y Acad Sci. 947:407-411,2001.PubMed
  4. Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y, Hoshijima M, Kaibuchi K, Takeshita A. Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo. Arterioscler Thromb Vasc Biol. 21:548-554,2001.PubMed
  5. Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Hiroki J, Kaibuchi K, Takeshita A. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 15:1062-1064,2001.PubMed
  6. Sato S, Ikegaki I, Asano T, Shimokawa H. Antiischemic properties of fasudil in experimental models of vasospastic angina. Jpn J Pharmacol. 87:34-40,2001.PubMed
  7. Shimokawa H, Morishige K, Miyata K, Kandabashi T, Eto Y, Ikegaki I, Asano T, Kaibuchi K, Takeshita A. Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo. Cardiovasc Res. 51:169-177,2001.PubMed
  8. Utsunomiya T, Satoh S, Ikegaki I, Toshima Y, Asano T, Shimokawa H. Antianginal effects of hydroxyfasudil, a Rho-kinase inhibitor, in a canine model of effort angina. Br J Pharmacol. 134:1724-1730,2001.PubMed
2000年
  1. Eto Y, Shimokawa H, Hiroki J, Morishige K, Kandabashi T, Matsumoto Y, Amano M, Hoshijima M, Kaibuchi K, Takeshita A. Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs. Am J Physiol Heart Circ Physiol. 278:H1744-1750,2000.PubMed
  2. 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 upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta. Circulation. 101:1319-1323,2000.PubMed
  3. Miyata K, Shimokawa H, Kandabashi T, Higo T, Morishige K, Eto Y, Egashira K, Kaibuchi K, Takeshita A. Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo. Arterioscler Thromb Vasc Biol. 20:2351-2358,2000.PubMed
  4. Shimokawa H. Cellular and molecular mechanisms of coronary artery spasm: lessons from animal models. Jpn Circ J. 64:1-12,2000.PubMed

(文責:福本義弘、田原俊介、佐藤公雄)

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