The roleof H_20_2as an endothelium-derived relaxing factors (EDRFs)

• Project Area: Signaling functions of reactive oxygen species
• Project/Area Number: 20117009
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku University
• Principal Investigator: SHIMOKAWA Hiroaki 東北大学, 大学院・医学系研究科, 教授 (00235681)
• Co-Investigator(Kenkyū-buntansha): SATOH Kimio 東北大学, 高等教育開発推進センター, 准教授 (80436120)
• Project Period (FY): 2008 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥105,040,000 (Direct Cost: ¥80,800,000、Indirect Cost: ¥24,240,000); Fiscal Year 2012: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2011: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2010: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000); Fiscal Year 2009: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000); Fiscal Year 2008: ¥23,400,000 (Direct Cost: ¥18,000,000、Indirect Cost: ¥5,400,000)
• Keywords: 血管内皮 / 内皮由来弛緩因子 / 一酸化窒素 / 過酸化水素 / 一酸化窒素合成酵素 / 活性酸素 / Rho/Rho-Kinase / メタボリックシンドローム / 臓器関連 / 酸化ストレス / 血管平滑筋 / Rho/Rho-kinase / 活性酵素 / Rho-kinase / 動脈硬化 / 一酸化窒素合成酵素(NOS) / 内皮由来過分極因子(EDHF)

Research Abstract

Oxidative stress, generated by excessive reactive oxygen species (ROS) promotes cardiovascular disease. However, the precise mechanism how ROS (i.e., H_20_2,0_2', and 'OH)deteriorate vascular function and promote vascular remodeling has not been clearly elucidated. Moreover, H_20_2 also plays a crucial role as a signaling molecule under physiological conditions. Our recent study revealed that H_20_2 is one of the endothelium-derived hyperpolarizing factor (EDHF) that contributes as a signaling molecule in the Vasculature.

Research Products

• [Journal Article] Statins exert pleiotropic effects through SmgGD S up-regulation with a resultant Rac l degradation (2013)
  • Author(s): Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, Takai Y, Williams CL, Liao JK, Shimokawa H
  • Journal Title: Arterioscter Thromz Vasc Biol Volume: (in press) Issue: 7 Pages: 1591-1600
  • DOI: 10.1161/atvbaha.112.300922
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications and prognostic impact-Multicenter registry study of the Japanese Coronary Spasm Association- (2013)
  • Author(s): 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
  • Journal Title: Eur Heart J Volume: 34 Pages: 258-267
  • Peer Reviewed
• [Journal Article] Plasma Cyclophilin A Is a Novel Biomarker for Coronary Artery Disease (2013)
  • Author(s): 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
  • Journal Title: Circulation Journal Volume: 77 Issue: 2 Pages: 447-455
  • DOI: 10.1253/circj.CJ-12-0805
  • NAID: 10031138924
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications and prognostic impact -Multicenter registrystudy of the Japanese Coronary Spasm Association- (2013)
  • Author(s): Takagi Y, Yasuda S, Takahashi J, TsunodaR, 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
  • Journal Title: Eur Heart J Volume: 34 Issue: 4 Pages: 258-267
  • DOI: 10.1093/eurheartj/ehs199
  • Peer Reviewed
• [Journal Article] Essential role of the bone marrow for microvascular endothelial and metabolic functions in mice (2012)
  • Author(s): Nakaj ima S, Ohashi J, Sawada A, Noda K, Fukumoto Y, Shimokawa H
  • Journal Title: Circ Res Volume: 111 Issue: 1 Pages: 87-96
  • DOI: 10.1161/circresaha.112.270215
  • Peer Reviewed
• [Journal Article] Mechanisms for Enhanced Endothelium-Derived Hyperpolarizing Factor-Mediated Responses in Microvessels in Mice (2012)
  • Author(s): Ohashi J, Sawada A, Nakjiima S, Noda K, Takaki A, Shimokawa H
  • Journal Title: Circulation Journal Volume: 76 Issue: 7 Pages: 1768-1779
  • DOI: 10.1253/circj.CJ-12-0197
  • NAID: 10030503846
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Long-term treatment with nifedipine suppresses coronary yperconstrcting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo: Possible involvement of Rho- kinase pathway- (2012)
  • Author(s): Tsuburaya R, Yasuda S, Shiroto T, Ito Y, Gao JY, Aizawa K, Kikuchi Y, Ito K, Takahashi J, Ishibashi-Ueda H, Shimokawa H
  • Journal Title: Eur Heart J Volume: 33 Pages: 791-799
  • Peer Reviewed
• [Journal Article] Long-term treatment with nifedipine suppresses coronary hyperconstrcting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo: Possible involvement of Rho-kinase pathway- (2012)
  • Author(s): Tsuburaya R, Yasuda S, Shiroto T, Ito Y, Gao JY, Aizawa K, Kikuchi Y, Ito K, Takahashi J, Ishibashi-Ueda H, Shimokawa H.
  • Journal Title: Eur Heart J Volume: 33 Issue: 6 Pages: 791-799
  • DOI: 10.1093/eurheartj/ehr145
  • Peer Reviewed
• [Journal Article] The Great East Japan Earthquake Disaster and cardiovascular diseases. (2012)
  • Author(s): Tatsuo Aoki
  • Journal Title: Eur Heart J. Volume: 33 Issue: 22 Pages: 2796-2803
  • DOI: 10.1093/eurheartj/ehs288
  • Peer Reviewed
• [Journal Article] Emergence of the erythropoietin/erythropoietin receptor system as a novel cardiovascular target (Review). (2012)
  • Author(s): Kimio Satoh
  • Journal Title: J Cardiovasc Pharmacol. Volume: 58 Issue: 6 Pages: 570-574
  • DOI: 10.1097/fjc.0b013e318235e7bb
  • Peer Reviewed
• [Journal Article] Mechanisms for enhanced endothelium-derived hyperpolarizing factor-mediated responses in microvessels in mice (2012)
  • Author(s): Ohashi J, Shimokawa H, et al
  • Journal Title: Circulation Journal Volume: (in press)
  • Peer Reviewed
• [Journal Article] Vascular-derived reactive oxygen species for homeostasis and diseases (2011)
  • Author(s): Satoh K, Shimokawa H
  • Journal Title: Nitric Oxide Volume: 25 Issue: 2 Pages: 211-215
  • DOI: 10.1016/j.niox.2011.04.005
  • Peer Reviewed
• [Journal Article] Rho-kinase:Important new therapeutic target in cardiovascular diseases (2011)
  • Author(s): Satoh K, Fukumoto Y, Shimokawa H
  • Journal Title: Am J Physiol Volume: 301 Issue: 2 Pages: 287-296
  • DOI: 10.1152/ajpheart.00327.2011
  • Peer Reviewed
• [Journal Article] Rho-kinase : Important new therapeutic target in cardiovascular disease (2011)
  • Author(s): Satoh K, Fukumoto Y, Shimokawa H
  • Journal Title: American Journal of Physiology Volume: 301 Pages: 287-296
  • Peer Reviewed
• [Journal Article] Long-term treatment with nifedipine suppresses coronary hypercon- stricting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo -Possible involve- ment of Rho-kinase pathway- (2011)
  • Author(s): Tsuburaya R, Yasuda S, Shimokawa H., et al.
  • Journal Title: Eur Heart J. in press
  • Peer Reviewed
• [Journal Article] Long-term treatment with nifedipine suppresses coronary hyperconstrcting responses and inflammatory changes induced by paclitaxel-eluting stent in pigs in vivo-Possible involvement of Rho-kinase pathway- (2011)
  • Author(s): Tsuburaya R, Yasuda S,…, Shimokawa H.
  • Journal Title: European Heart Journal Volume: (未定 In press)
  • Peer Reviewed
• [Journal Article] Erythropoietin enhances hydrogen peroxide- mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in dogs in invio. (2010)
  • Author(s): Yada T, Shimokawa H, Hiramatsu O, et al.
  • Journal Title: Am J Physiol. 299
  • Peer Reviewed
• [Journal Article] Combination therapy with olmesartan and azelnidipine improves EDHF-mediated responses in diabetic Apolipoprotein E-deficient mice. (2010)
  • Author(s): Hosoya M, Ohashi J, Shimokawa H.
  • Journal Title: Circ J. 74 Pages: 798-806
  • Peer Reviewed
• [Journal Article] Erythropoietin enhances hydrogen peroxide-mediated dilatation of canine coronary collateral arterioles during myocardial ischemia in dogs in vivo. (2010)
  • Author(s): Yada T, Shimokawa H, Hiramatsu O, et al.
  • Journal Title: American Journal of Physiology Volume: 299
  • Peer Reviewed
• [Journal Article] Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. (2010)
  • Author(s): Shimokawa H.
  • Journal Title: European Journal of Physiology Volume: 459 Pages: 915-922
  • Peer Reviewed
• [Journal Article] Double-blind and placebo-controlled study of the effectiveness and safety of extra corporeal cardiac shock wave therapy for severe angina pectoris (2010)
  • Author(s): Kikuchi Y, Shimokawa H, et al.
  • Journal Title: Circulation Journal 74 Pages: 589-591
  • Peer Reviewed
• [Journal Article] Importance of Rac1 signaling pathway inhibition in the pleiotropic effects of HMG-CoA reductase inhibitors. (2009)
  • Author(s): Rashid M, Tawara S, Shimokawa H.
  • Journal Title: Circ J. 73 Pages: 361-370
  • Peer Reviewed
• [Journal Article] Evidence for Rho-Kinase Activation in Patients With Pulmonary Arterial Hypertension (2009)
  • Author(s): Zhulanqiqige Do., Shimokawa H, et al.
  • Journal Title: Circulation Journal 73 Pages: 1731-1739
  • Peer Reviewed
• [Journal Article] Role of Rho-kinase in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stent in pies in vivo (2009)
  • Author(s): Shiroto T, Shimokawa H, et al.
  • Journal Title: Journal of American College Cardiology 54 Pages: 2321-2329
  • Peer Reviewed
• [Journal Article] Crucial role of endothelial nitric oxide syntahses systen in endothelium- dependent hyperpolarization in mice. (2008)
  • Author(s): Takaki A, Morikawa K, Shimokawa H.
  • Journal Title: J Exp Med. 205 Pages: 2053-2063
  • Peer Reviewed
• [Journal Article] Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice (2008)
  • Author(s): Takaki A, Morikawa K, Tsutsui M, Murayama Y, Tekes E, Yamagishi H, Ohashi J, Yada T, Yanagihara N, Shimokawa H
  • Journal Title: The Journal of experimental medicine 205(9) Pages: 2053-2063
  • Peer Reviewed
• [Journal Article] Roles of endothelial oxidases in endothelium-derived hyperpolarizing factor responses in mice (2008)
  • Author(s): Takaki A, Morikawa K, Murayama Y, Yamagishi H, Hosoya M, Ohashi J, Shimokawa H
  • Journal Title: Journal of cardiovascular pharmacology 52(6) Pages: 510-517
  • Peer Reviewed
• [Journal Article] Bone-marrow-derived matrix metalloproteinase-14 : a novel target for plague stability (2008)
  • Author(s): Shimokawa H
  • Journal Title: Circulation 117(9) Pages: 863-865
  • Peer Reviewed
• [Presentation] Role ofRho/Rho-kinase pathway in the cardiovascular system (2012)
  • Author(s): Shimokawa H
  • Organizer: 6th European Congress of Pharmacology <Main Session:Rho/Rho-kinase Signaling in Health and Diseases>
  • Place of Presentation: Granada, Spain
  • Year and Date: 2012-07-19
• [Presentation] Update on coronary spasm (2012)
  • Author(s): Shimokawa H
  • Organizer: Rome Cardiology Forum 2012, <Symposium:Update on coronary vasomotlon>
  • Place of Presentation: Rome, Italy
  • Year and Date: 2012-05-30
• [Presentation] Rho-kinase as an important new therapeutic target in cardiovascular medicine (2012)
  • Author(s): Shimokawa H
  • Organizer: Invited Lecture at the San Raffaele University
  • Place of Presentation: Milano, Italy
  • Year and Date: 2012-05-30
• [Presentation] Present status & future perspectives ofheart failure in Japan (2012)
  • Author(s): Shimokawa H
  • Organizer: Invited lecture at the Flinders Medical Center
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2012-05-02
• [Presentation] Coronary spasm in 2012: Mechanisms and treatment (2012)
  • Author(s): Shimokawa H
  • Organizer: Invited lecture at the Cardiac Society of Australia & New Zealand Meeting
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2012-05-01
• [Presentation] Rho-kinase as an important CV therapeutic target (2012)
  • Author(s): Shimokawa H
  • Organizer: Invited lecture at Medical Grand Round of the Queen Elizabeth Hospital
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2012-05-01
• [Presentation] Recent progress in endothelial research (2012)
  • Author(s): Shimokawa H
  • Organizer: Invited lecture at the Cardiology Academic Meeting of the Queen Elizabeth Hospital
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2012-05-01
• [Presentation] Recent progress in endothelial research (2012)
  • Author(s): Shimokawa H
  • Organizer: Invited lecture at Royal Adelaide Hospital
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2012-04-30
• [Presentation] Coronary spasm in 2012: Mechanisms and treatment. (2012)
  • Author(s): Hiroaki Shimokawa
  • Organizer: Invited lecture at the Cardiac Society of Australia & New Zealand Meeting
  • Place of Presentation: Adelaide, Australia
  • Year and Date: 2012-04-30
  • Invited
• [Presentation] Symposium: Update on coronary vasomotion (2012)
  • Author(s): Hiroaki Shimokawa
  • Organizer: Rome Cardiology Forum 2012
  • Place of Presentation: Rome, Italy
  • Year and Date: 2012-04-01
  • Invited
• [Presentation] The Great East Japan Earthquake Disaster and cardiovascular diseases (2012)
  • Author(s): Shimokawa H
  • Organizer: European Society of Cardiology Congress 2012 <Hotline Session>
  • Place of Presentation: Munich, Germany
• [Presentation] Multiple mechanisms are involved in enhanced endothelium-derived hyperpolarizing factor (EDHF)-mediated responses in microvessels in mice-A clue for novel strategy for vascular protection- (2011)
  • Author(s): Ohashi J, Shimokawa H, et al
  • Organizer: American Heart Association
  • Place of Presentation: Orlando, USA
  • Year and Date: 2011-11-12
• [Presentation] Rho-kinase as a new therapeutic target in cardiovascular medicine. (2010)
  • Author(s): Shimokawa H.
  • Organizer: The 54^<th> Annual Scientific Meeting of the Korean Society of Cardiology (October 7-9, 2010, Seoul, Korea)
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2010-10-08
• [Presentation] Endothelial research for 25 years : From regenerated endothelium to triple NOSs-deficient mice. (2010)
  • Author(s): Shimokawa H.
  • Organizer: 4^<th> Scientific Meeting of the Asian Society for Vascular Biology
  • Place of Presentation: HK(Invited lecture)
• [Presentation] Non-invasive revascularization by CSWT in chronic ischemia ; animal and clinical studies (2009)
  • Author(s): Shimokawa H
  • Organizer: European Society of Cardiology Congress 2009
  • Place of Presentation: スペイン バルセロナ
  • Year and Date: 2009-08-29
• [Presentation] Rho-kinase is an important therapeutic target in cardiovascular medicine (2009)
  • Author(s): Shimokawa H
  • Organizer: International Symposium on Atherosclerosis
  • Place of Presentation: アメリカ ボストン
  • Year and Date: 2009-06-01
• [Book] 日本人の虚血性心疾患に関 する基礎的・臨床的研究 (日本医師会医 学賞受賞記念総説) (2013)
  • Author(s): 下川宏明
  • Publisher: 日本医師会雑 誌
• [Book] エリスロポエチンの血管内皮保護作用と血管恒常性維持機構 (2013)
  • Author(s): 佐藤公雄、下川宏明
  • Publisher: BIO Clinica.
• [Book] 内皮由来過分極因子の医学的意義.血栓と循環 (2012)
  • Author(s): 下川宏明、神戸茂雄
  • Publisher: メディカルレビュー社
• [Book] 大震災と循環器・呼吸器疾患(序文).呼吸と循環 (2012)
  • Author(s): 下川宏明
  • Publisher: 医学書院
• [Book] H_20_2が制御する血管弛緩反応.日本薬理学雑誌 (2012)
  • Author(s): 下川宏明
  • Publisher: 日本薬理学会
• [Book] 肺高血圧診療の進歩をみる. 特集にあたって.Vascular Medicine (2012)
  • Author(s): 下川宏明
  • Publisher: 先端医学社
• [Book] H2O2が制御する血管弛緩反応 (2012)
  • Author(s): 下川宏明
  • Total Pages: 232
  • Publisher: 日本薬理学雑誌
• [Book] 医学論文の書き方-Circulation Journal編集長からのアドバイス-心臓 (2011)
  • Author(s): 下川宏明
  • Publisher: 日本心臓財団・日本循環器学会
• [Book] Annual Review循環器 (2011)
  • Author(s): 福本義弘、下川宏明
  • Publisher: 肺高血圧症に対するRhoキナーゼ阻害薬の治療効果
• [Book] 冠循環・心筋虚血の発生機序 (2010)
  • Author(s): 安田聡、下川宏明
  • Publisher: 最新医学社
• [Book] H2O2が制御する血管弛緩反応の分子機構(谷口直之(編)) (2009)
  • Author(s): 佐藤公雄、下川宏明
  • Publisher: 実験医学
• [Book] Acta Physiologica(Endothelial dysfunction and vascular disease) (2009)
  • Author(s): Vanhoutte PM, Shimokawa H, et al.
• [Remarks]
• [Remarks] 血管機能調節のネットワーク機構を解明（東北大学）
• [Remarks]
  • URL: http://www.cardio.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学循環器内科HP
  • URL: http://www.cardio.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学循環器内科HP
  • URL: http://www.cardio.med.tohoku.ac.jb/index.html
• [Patent(Industrial Property Rights)] サイクロフィリンAによる心血管疾患の検査方法 (2012)
  • Inventor(s): 川宏明、佐藤公雄
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄(国立大学法人東北大学)
  • Industrial Property Number: 2012-239615
  • Filing Date: 2012-10-30
• [Patent(Industrial Property Rights)] 「サイクロフィリンＡによる心血管疾患の検査方法」 (2012)
  • Inventor(s): 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-239615
  • Filing Date: 2012-10-30
• [Patent(Industrial Property Rights)] スタチンの用法、用量を決定する方法 (2011)
  • Inventor(s): 下川宏明、田中眞一
  • Industrial Property Rights Holder: 下川宏明、田中眞一
  • Industrial Property Number: 2011-197906
  • Filing Date: 2011-09-12