新しいＲｈｏ－ｋｉｎａｓｅ阻害薬による肺高血圧治療効果の検討

• Project/Area Number: 14F04902
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 外国
• Research Field: Cardiovascular medicine
• Research Institution: Tohoku University
• Principal Investigator: 下川 宏明 東北大学, 医学系研究科, 教授 (00235681)
• Co-Investigator(Kenkyū-buntansha): AL-MAMUN MD. ELIAS 東北大学, 医学(系)研究科(研究院), 外国人特別研究員 ; AL-MAMUN MD. ELI ; AL-MAMUN M.
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,200,000 (Direct Cost: ¥2,200,000); Fiscal Year 2016: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 2015: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 2014: ¥800,000 (Direct Cost: ¥800,000)
• Keywords: 循環器・高血圧 / 肺高血圧症

Outline of Annual Research Achievements

Al-mamun先生と共同して実施している研究は、新規Rho-kinase選択的阻害剤の作用機序、特に、我々が世界に先駆けて発見・同定した内皮機能における役割や血管平滑筋での作用機序の解明である。特にAl-mamun先生は、薬理学的な詳細な検討技術に優れており、薬剤間の作用機序の差異を検討することと、細胞増殖のシグナル機構として重要なERK1/2に関して、遺伝子改変マウスを用いた肺高血圧症の解明を進めている。さらに、血管内皮特異的遺伝子欠損マウスを作製する準備も進めており、新たな知見が得られることが期待される。　Al-mamun先生との共同研究の意義としては、これらの一連の研究により、心血管系の恒常性の破綻におけるRho-kinaseの重要性が明らかになるとともに、糖尿病をはじめとした代謝性疾患における内皮機能不全の分子機構の解明や新たな治療法の開発に結びつくことが期待される。これまで肺高血圧の病態には血管平滑筋増殖にばかり注目が集まっていたが、我々や他の研究グループにより、血管内皮機能の重要性が普遍的に認められることが明らかになってきた。Al-mamun先生との共同研究で、そうしたこれまで全く知られていなかったRho-kinaseによる内皮機能の調節機構が明らかになりつつある。具体的には、以下の検討を行ってきた。(A) 遺伝子改変マウス（ROCK1, ROCK2欠損マウス）を用いた動物モデルを用いた、各アイソタイプの役割に関する詳細なメカニズムの解明。 (B) ヒト肺動脈構築細胞におけるRho-kinase発現とそのシグナル伝達機構（１）ヒト肺動脈血管平滑筋細胞を用いた酸化ストレス増幅系の解明（細胞実験）（２）ヒト肺動脈血管内皮細胞への炎症シグナル伝達機構の解明（細胞実験）

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] Selenoprotein P promotes vascular smooth muscle cell proliferation and pulmonary hypertension -A possible novel therapeutic target- (2018)
  • Author(s): Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Md. Elias Al-Mamun, Mohammad Abdul Hai Siddique, Omura J, Satoh T, Nogi M, Sunamura S, Miyata S, Shimokawa H.
  • Journal Title: Circulation Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. (2018)
  • Author(s): Kozu K, Sugimura K, Aoki T, Tatebe S, Yamamoto S, Yaoita N, Shimizu T, Nochioka K, Sato H, Konno R, Satoh K, Miyata S, Shimokawa H.
  • Journal Title: Heart Vessels. Volume: in press Issue: 8 Pages: 939-947
  • DOI: 10.1007/s00380-018-1140-6
  • Peer Reviewed / Open Access
• [Journal Article] Shrinking basic cardiovascular research in Japan: A tip of the iceberg. (2017)
  • Author(s): Shimokawa H, Kikuchi N, Satoh K.
  • Journal Title: Circ Res. Volume: 121 Issue: 4 Pages: 331-334
  • DOI: 10.1161/circresaha.117.310845
  • Peer Reviewed / Open Access
• [Journal Article] Activated TAFI promotes the development of chronic thromboembolic pulmonary hypertension -A possible novel therapeutic target- (2017)
  • Author(s): Satoh T, Satoh K, Yaoita N, Kikuchi N, Omura J, Kurosawa R, Numano K, Md. Elias-Al-Mamun, Mohammad Abdul Hai Siddique, Sunamura S, Nogi M, Suzuki K, Miyata S, Morser J, Shimokawa H.
  • Journal Title: Circ Res. Volume: 120 Issue: 8 Pages: 1246-1262
  • DOI: 10.1161/circresaha.117.310640
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice (2016)
  • Author(s): 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.
  • Journal Title: Circ Res. Volume: 119 Issue: 2 Pages: 197
  • DOI: 10.1161/circresaha.115.308178
  • URL: https://localhost/en/publications/76b7841d-be9c-4108-9be3-5f6c974614e7
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thrombin-activatable fibrinolysis inhibitor in chronic thromboembolic pulmonary hypertension. (2016)
  • Author(s): Yaoita N, Satoh K, Satoh T, Sugimura K, Tatebe S, Yamamoto S, Aoki T, Miura M, Miyata S, Kawamura T, Horiuchi H, Fukumoto Y, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 36 Issue: 6 Pages: 1293-1301
  • DOI: 10.1161/atvbaha.115.306845
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel therapeutic targets of pulmonary hypertension. (2016)
  • Author(s): Yaoita N, Satoh K, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 36 Issue: 12
  • DOI: 10.1161/atvbaha.116.308263
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RhoA/Rho-kinase in the cardiovascular system. (2016)
  • Author(s): Shimokawa H, Sunamura S, Satoh K.
  • Journal Title: Circ Res. Volume: 118 Issue: 2 Pages: 352-366
  • DOI: 10.1161/circresaha.115.306532
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Selenoprotein P promotes the development of pulmonary arterial hypertension-A Possible Novel Therapeutic Target- (2018)
  • Author(s): Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Abdul Hai Siddique M, Omura J, Satoh T, Nogi M, Sunamura S, Miyata S, Saito Y, Hoshikawa Y, Okada Y, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension (2018年2月27～3月1日, Nice, France)
  • Int'l Joint Research
• [Presentation] ADAMTS8 Promotes the Development of pulmonary arterial hypertension and right ventricular failure-A possible novel therapeutic target- (2018)
  • Author(s): Satoh K, Omura J, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Sunamura S, Ohtsuki T, Elias-Al-Mamun M, Abdul Hai Siddique M, Yaoita N, Miyata S, Hoshikawa Y, Okada Y, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension (2018年2月27～3月1日, Nice, France)
  • Int'l Joint Research
• [Presentation] Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension -High-throughput screening of 5,562 compounds- (2018)
  • Author(s): Kurosawa R, Satoh K, Kikuchi N, Satoh T, Omura J, Nogi M, Sunamura S, Ohtsuki T, Yaoita N, Abdul Hai Siddique M, Elias-Al-Mamun M, Shimizu T, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension (2018年2月27～3月1日, Nice, France)
  • Int'l Joint Research
• [Presentation] Different roles of myocardial ROCK1 and ROCK2 in response to chronic pressure-overload in mice. (2018)
  • Author(s): Sunamura S, Satoh K, Shimizu T, Suzuki K, Ikeda S, Kudo S, Omura J, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Ohtsuki T, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension (2018年2月27～3月1日, Nice, France)
  • Int'l Joint Research
• [Presentation] Identification of Emetine as a Novel Therapeutic Agent for Pulmonary Hypertension in Rats -High-throughput Screening of 5,562 Compounds- (2018)
  • Author(s): Abdul Hai Siddique M, Satoh K, Kurosawa R, Elias-Al-Mamun M, Kikuchi N, Omura J, Satoh T, Nogi M, Sunamura S, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension (2018年2月27～3月1日, Nice, France)
  • Int'l Joint Research
• [Presentation] Recent progress in vascular biology on pulmonary hypertension. (2016)
  • Author(s): Shimokawa H.
  • Organizer: 7th Scientific Meeting of the Asian Society of Vascular Biology
  • Place of Presentation: Taiwan, Republic of China
  • Year and Date: 2016-10-27
  • Int'l Joint Research / Invited
• [Book] Diagnosis and Treatment of Pulmonary Hypertension. From Bench to Bedside (2017)
  • Author(s): Satoh K, Sugimura K, Shimokawa H.
  • Total Pages: 236
  • Publisher: Springer Nature, Singapore