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(7)血管生物学(血管内皮)

血管内皮細胞は、血管内腔を覆う単なる一層の細胞群ではなく、多くの機能を有していることが知られています。中でも血管内皮はプロスタサイクリン(PGI2) ・一酸化窒素(NO)・内皮由来過分極因子(endothelium-derived hyperpolarizing factor, EDHF)の3種類の血管弛緩因子を産生・放出し、血管機能の恒常性の維持に重要な役割を果たしています。この3種類の弛緩因子のうちPGI2とNOはすでに同定され、一部では臨床応用も行われています。しかし、第3の因子であるEDHFに関しては、1988年にその存在が提唱されて以来、その本体として数種類の物質や機序が提唱されており、いまだ不明な点が多く残されています。血管生物学グループでは、この第3の因子であるEDHFに関する研究をおこなっています。

EDHFについて

EDHFは、血管内皮細胞に対するアゴニスト刺激やずり応力などの様々な刺激により内皮から産生・遊離され、血管平滑筋に作用して血管平滑筋膜のカルシウム活性型Kチャネル(KCaチャネル)を開口し、血管平滑筋の細胞膜を過分極させることにより血管平滑筋の弛緩を惹起します。このEDHFは血管弛緩反応に関する役割をNOと分担しており、大動脈などの導管血管における弛緩反応は主としてNOにより制御されていますが、EDHFは大血管よりも微小血管、特に抵抗血管において重要な役割を果たしています。
EDHF本体については動物種、あるいは同一個体内でも血管床(臓器差)・血管径により差がみられ、異なる動物種、あるいは異なる血管床、さらには同一血管床でも血管径の差により異なったEDHFが存在する可能性が示唆されています。また、EDHFの本体については、その発見以来、様々な説が提唱されてきましたが、いずれも広い支持を得るまでには至っていません。これまでに報告されたEDHF本体に関する仮説のうち代表的なものには、(1) cytochrome P450 epoxygenaseを介してアラキドン酸から産生されるepoxyeicosatrienoic acids (EETs)であるとする説、(2)Kイオン説、(3)Gap junction説、そして(4)我々が提唱している過酸化水素(H2O2)説があります。いずれの説も、それだけでは説明がつかない血管床が存在するため、現在のところ複数のEDHFの存在が示唆されています(図1)。

研究内容

我々はこれまでに、血管内皮由来の生理的濃度の過酸化水素(H2O2)がマウス及びヒト腸間膜動脈、ブタ冠微小血管におけるEDHFの本体であることを初めて同定し、EDHFとしてのH2O2の産生には、内皮型一酸化窒素合成酵素(eNOS)から生理的に産生・遊離されるsuperoxideが内皮Cu,Zn-superoxide dismutase (Cu,Zn-SOD)によりH2O2に変換されEDHFとして血管弛緩反応を惹起していることを明らかにしました。さらに我々は、EDHFによる弛緩反応が、糖尿病や高脂血症などの種々の動脈硬化危険因子により障害されることも報告しており、NO以外の活性酸素種の一つであるH2O2が血管弛緩反応において重要な役割を果たしていることを明らかにしています(図2)。

我々が提唱しているEDHF/H2O2説のさらなる解明を目指し、現在、以下のテーマについて研究を行っています。

  • 一酸化窒素合成酵素の各種アイソフォームの心血管病の成因における役割に関する研究
    近年我々は、生体内に存在する内皮型・神経型・誘導型の3種類すべてのNO合成酵素遺伝子を完全欠損させたトリプルNOSノックアウトマウスの作製に世界で初めて成功しました。このマウスは、自然発症の急性心筋梗塞・腎病変が生じ、生命予後も図3極めて悪いことが報告されています。このトリプルNOSノックアウトマウスを用いた検討によってマウス腸間膜微小動脈では、NO反応とEDHF反応の両反応が共に消失していることが明らかになり(図3)、NO合成酵素系とEDHF反応との密接な関与が世界で初めて証明されました。現在、この研究をさらに発展させ、トリプルNOSノックアウトマウスを用いて内皮由来弛緩因子(NO, EDHF/H2O2)の臨床的意義の解明を目指し研究を行っています。
  • 循環作動薬の内皮由来過分極因子(EDHF)に及ぼす効果
    これまでに動脈硬化などの様々な病態による内皮機能障害に伴いEDHFを介した弛緩反応が低下することが報告されています。一方、アンギオテンシン変換酵素(ACE)阻害薬の慢性投与によりEDHF反応は増強されることも報告されています。我々はその増強されたEDHF弛緩反応にH2O2が関与していることを明らかにしました。これらの研究をさらに発展させ、本研究では、動脈硬化等の病態モデル動物を用い、ACE阻害薬、アンギオテンシン1a受容体拮抗薬(ARB)、カルシウム拮抗薬等の各種循環作動薬の血管反応性の改善におけるEDHF反応の関与およびその作用機序の検討を行っています。
  • eNOSの血管径による機能変化の分子機構の解明
    NOとEDHFの間には血管径による明らかな役割分担があり、NOはより太い血管で、EDHFは微小血管で重要な役割を果たしています。近年、我々は、NO合成酵素系由来のsuperoxideがEDHF/H2O2として働くことを報告し、NO合成酵素系は血管径のサ図4イズの違いにより大血管ではNO合成酵素として、小血管ではEDHF合成酵素として重要な役割を果たしていることを明らかにし、NO合成酵素系における新たな概念を提唱しました (図4)。本研究では、この概念に基づき、血管径によるNOSの機能変化を解明するためマウス大動脈と腸間膜微小血管を用い、eNOS活性系・eNOS補酵素系・superoxide消去系について研究を行っています。
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. DOI 10.1007/s00125-017-4259-6.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. (in press)
  5. Satake Y, Satoh K, Nogi M, Omura J, Godo S, Miyata S, Saito H, Tanaka S, Ikumi Y, Yamashita S, Kaiho Y, Tsutsui M, Arai Y, Shimokawa H. Crucial roles of nitric oxide synthases in ss-adrenoceptor-mediated bladder relaxation in mice. Am J Physiol. 312:F33-F42,2017.PDF
  6. 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. Akata K, Yatera K, Wang KY, Naito K, Ogoshi T, Noguchi S, Kido T, Toyohira Y, Shimokawa H, Yanagihara N, Tsutsui M, Mukae H. Decreased bronchial eosinophilic inflammation and mucus hypersecretion in asthmatic mice lacking all nitric oxide synthase isoforms. Lung. 194:121-124,2016. PDF
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-kinase in the cardiovascular system. Circ Res. 118:352-366,2016.PDF
  9. Shimokawa H, Godo S. Diverse functions of endothelial NO synthases system: NO and EDH. J Cardiovasc Pharmacol. 67:361-366,2016.PDF
  10. Shindo T, Ito K, Ogata T, Hatanaka K, Kurosawa R, Eguchi K, Kagaya Y, Hanawa K, Aizawa K, Shiroto T, Kasukabe S, Miyata S, Taki H, Hasegawa H, Kanai H, Shimokawa H. Low-intensity pulsed ultrasound enhances angiogenesis and ameliorates left ventricular dysfunction in a mouse model of acute myocardial infarction. Arterioscler Throm Vasc Biol. 36:1293-1301,2016.PubMed
  11. 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
  12. Yahata K, Kanno H, Ozawa H, Yamaya S, Tateda S, Ito K, Shimokawa H, Itoi E. Low-energy extracorporeal shock wave therapy promotes VEGF expression and angiogenesis and improves locomotor and sensory functions after spinal cord injury. J Neurosurg Spine. 1:1-11,2016.PDF
  13. 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
  14. 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. Nishimiya K, Matsumoto Y, Shindo T, Hanawa K, Hasebe Y, Tsuburaya R, Shiroto T, Takahashi J, Ito K, Ishibashi-Ueda H, Yasuda S, Shimokawa H. Association of adventitial vasa vasorum and inflammation with coronary hyperconstriction after drug-eluting stent implantation in pigs in vivo. Circ J. 79:1787-1798,2015.PDF
  2. 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
  3. 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
  4. Satoh K. Cyclophilin A in cardiovascular homeostasis and diseases. Tohoku J Exp Med. 235:1-15,2015.PDF
  5. 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
  6. Shimokawa H, Satoh K. Light and dark of reactive oxygen species for vascular function. J Cardiovasc Pharmacol. 65:412-418,2015.PubMed
  7. 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. Hanawa K, Ito K, Aizawa K, Shindo T, Nishimiya K, Hasebe Y, Tsuburaya R Hasegawa H, Yasuda S, Kanai H, Shimokawa H. Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia. PLoS One. 2014;9(8):e104863.PDF
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Shimokawa H. 2014 William Harvey Lecture. Importance of coronary vasomotion abnormalities -From bench to bedside- Eur Heart J. 35:3180-3193,2014.PDF
  12. Shimokawa H, Satoh K. Recent Highlights of ATVB: Vascular function. Arteriosclr Thromb Vasc Biol. 34:2359-2362,2014.
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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. 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
  3. 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
  4. 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
  5. 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. Hosoya M, Ohashi J, Sawada A, Takaki A, Shimokawa H. Combination therapy with olmesartan and azelnidipine improves EDHF-mediated responses in diabetic apolipoprotein E-deficient mice. Circ J. 74:798-806,2010.PubMed
  2. 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
  3. 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
  4. Ohashi J, Shimokawa H. Novel mechanism of vasodilatation. Nippon Rinsyo. 68:631-635,2010. Japanese.PubMed
  5. 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
  6. Satoh K, Shimokawa H, Berk BC. Cyclophilin A: promising new target in cardiovascular therapy. Circulation J. 74:2249-2256,2010. (review)PubMed
  7. Shimokawa H. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pflugers Arch. 459:915-922,2010.PubMed
  8. Shimokawa H, Tsutsui M. Nitric oxide synthases in the pathogenesis of cardiovascular disease: lessons from genetically modified mice. Pflugers Arch. 459:959-967,2010.PubMed
  9. 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
  10. Talukder MA, Yang F, Shimokawa H, Zweier JL. eNOS is required for acute in vivo ischemic preconditioning of the heart: effects of ischemic duration and sex. Am J Physiol Heart Circ Physiol. 299:H437-445,2010.PubMed
  11. Yada Y, Shibata K, Fukuno Y, Sabanai K, Morisada N, Nakata S, Morishita T, Toyohira Y, Wang KY, Tanimoto A, Sasaguri Y, Tasaki H, Nakashima Y, Shimokawa H, Yanagihara N, Otsuji Y, Tsutsui M. Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet. Cardiovasc Res. 299:H1928-1935,2010.PubMed
2009年
  1. Do E 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. 73:1731-1739,2009.PubMed
  2. 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.PDF
  3. 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
  4. 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
  5. Shiroto T, Yasuda S, Tsuburaya R, Ito Y, Takahashi J, Ito K, Ishibashi-Ueda H, Shimokawa H. Role of Rho-kinase in the pathogensis of coronary hyperconstricting responses induced by drug-eluting stents in pigs in vivo. J Am Coll Cardiol. 54:2321-2329,2009.PubMed
  6. Tsutsui M, Shimokawa H, Otsuji Y, Ueta Y, Sasaguri Y, Yanagihara N. Nitric oxide synthases and cardiovascular disease: insights from genetically modified mice. Circ J. 73:986-993,2009.PubMed
  7. Vanhoutte PM, Shimokawa H, Tang EH, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol(Oxf). 196:193-222,2009.PubMed
2008年
  1. Nakata S, Tsutsui M, Shimokawa H, Suda O, Morishita T, Shibata K, Yatera Y, Sabanai K, Tanimoto A, Nagasaki M, Tasaki, H., Sasaguri Y, Nakashima Y, Otsuji Y, Yanagihara N. Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation. 117:2211-2223,2008.PubMed
  2. 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
  3. Sabanai K, Tsutsui M, Sakai A, Hirasawa H, Tanaka S, Nakamura E, Tanimoto A, Sasaguri Y, Ito M, Shimokawa H, Nakamura T, Yanagihara, N. Genetic disruption of all NO synthase isoforms enhances BMD and bone turnover in mice in vivo: involvement of the renin-angiotensin system. J Bone Miner Res. 23:633-643,2008.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. Shimokawa, H. Bone-marrow-derived matrix metalloproteinase-14: a novel target for plaque stability. Circulation. 117:863-865,2008.PubMed
  7. Takaki A, Morikawa K, Murayama Y, Tekes E, Yamagishi H, Ohashi J, Tsutsui M, Yada T, Yanagihara N, Shimokawa H. Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med. 205:2053-2063,2008.PubMed
  8. 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. 52:510-517,2008.PubMed
  9. Tsutsui M, Nakata S, Shimokawa H, Otsuiji Y, Yanagihara N. Spontaneous myocardial infarction and nitric oxide synthase. Trends Cardiovasc Med. 18:275-279,2008.PubMed
  10. 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
  11. Yada T, Shimokawa H, Morikawa K, Takaki A, Shinozaki Y, Mori H, Goto M, Ogasawara Y, Kajiya F. Role of Cu,Zn-SOD in the synthesis of endogenous vasodilator hydrogen peroxide during reactive hyperemia in mouse mesenteric microcirculation in vivo. Am J Physiol Heart Circ Physiol. 294:H441-448,2008.PubMed
2007年
  1. 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
  2. Yada T, Shimokawa H, Hiramatsu O, Shinozaki Y, Mori H, Goto M, Ogasawara Y, Kajiya F. Important role of endogenous hydrogen peroxide in pacing-induced metabolic coronary vasodilation in dogs in vivo. J Am Coll Cardiol. 50:1272-1278,2007.PDF
2006年
  1. 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. 102:10616-10621,2006.PubMed
  2. 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
  3. Shimokawa H. & Morikawa K. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Mol Cell Cardiol. 39:725-732,2006.PubMed
  4. Takaki, A. & Shimokawa, H. Endothelium-derived hyperpolarizing factor and endothelium dysfunction. Nippon. Rinsho. 64,Suppl 5:240-243,2006.PubMed
  5. Yada T, Shimokawa H, Hiramatsu O, Haruna, Y, Morita Y, Kashihara N, Shinozaki Y, Mori H, Goto M, Ogasawara Y, Kajiya F. Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo. Am J Physiol. 291:H1138-H1146,2006.PubMed
2005年
  1. Fujiki T, Shimokawa H, Morikawa K, Kubota H, Hatanaka M, Talukder, M.A, Matoba T, Takeshita A, Sunagawa K. Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin-converting enzyme inhibitor on endothelium-derived hyperpolarizing factor-mediated responses in mice. Arterioscler Thromb Vasc Biol. 25:766-771,2005.PubMed
  2. Morikawa K, Matoba T, Kubota H, Hatanaka M, Fujiki T, Takahashi S, Shimokawa H. Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice. J Cardiovasc Pharmacol. 45:485-490,2005.PubMed
2004年
  1. 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. 44:552-556,2004.PubMed
  2. Shimokawa H, Matoba T. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res. 49:543-549,2004.PubMed
2003年
  1. Matoba T, Shimokawa H, Morikawa K, Kubota H, Kunihiro I, Urakami H.L, Mukai Y, Hirakawa Y, Akaike T, Tkakeshita A. Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels. Arterioscler Thromb Vasc Biol. 23:1224-1230,2003.PubMed
  2. Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder M.A, Hatanaka M, Fujiki T, Maeda H, Takahashi S, Takeshita A. Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest. 112:1871-1879,2003.PubMed
  3. Shimokawa H. & Matoba T. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Pharmacol Sci. 92:1-6,2003.PubMed
  4. 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. 107:1040-1045,2003.PubMed
2002年
  1. 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. 290:909-913,2002.PubMed
2000年
  1. 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. 106:1521-1530,2000.PubMed

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