Development of novel therapeutic target in chronic thromboembolic pulmonary hypertension

• Project/Area Number: 15K19360
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tohoku University
• Principal Investigator: Yaoita Nobuhiro 東北大学, 東北メディカル・メガバンク機構, 助教 (00735368)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 循環器・高血圧 / 肺高血圧症 / 血栓 / 線溶系

Outline of Final Research Achievements

The clot of chronic thromboembolic pulmonary hypertension (CTEPH) patients was more resistant to fibrinolysis than that of non-PH patients or pulmonary arterial hypertension (PAH)patients. The plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) and the activation of TAFI were increased in CTEPH patients. Moreover, SNPs of cpb2, which induced the plasma levels of TAFI, was found in CTEPH patients. The impairment of fibrinolysis in CTEPH patients was inmproved with the inhibitor of avtivated TAFI.
In the TAFI overexpression mice, pulmonary hypertension was worse than wild type mice with hypoxic exposure and organaized thrombi ws found in pulmonary artery. Moreoover, TAFI increased the proliferation of smooth muscle cells of human.
These data suggest that TAFI could be a novel biomarker and realistic therapeutic target of CTEPH.

Research Products

• [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, Elias-Al-Mamun M, AbdulHai Siddique MAH, Sunamura S, Nogi M, Suzuki K, Miyata S, John Morser J, Shimokawa H.
  • Journal Title: Circ Res. Volume: 印刷中
  • 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, Kawamura T, Horiuchi H, Fukumoto Y, Shimokawa H.
  • Journal Title: Arterioscler Throm Vasc Biol. Volume: 36 Pages: 1293-1301
  • Peer Reviewed / Open Access / 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Multiple Beneficial Effects of Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension (2016)
  • Author(s): Tatebe S, Sugimura K, Aoki T, Miura M, Nochioka K, Miyamichi-Yamamoto S, Yaoita N, Suzuki H, Sato H, Satoh K, Fukumoto Y, Shimokawa H.
  • Journal Title: Circulation Journal Volume: 80 Issue: 4 Pages: 980-988
  • DOI: 10.1253/circj.CJ-15-1212
  • NAID: 130005139581
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Thrombin Activatable Fibrinolysis Inhibitor Promotes Development of Chronic Thromboembolic Pulmonary Hypertension-A Possible Novel Therapeutic Target. (2016)
  • Author(s): T Satoh, K Satoh, N Yaoita, N Kikuchi, J Omura, R Kurosawa, S Sunamura, M Nogi, T Otsuki, K Numano, Elias Al-Mamun, Mohammad Abdul Hai Siddique, S Tatebe, T Aoki, K Sugimura, J Morser, H Shimokawa
  • Organizer: アメリカ心臓病学会
  • Place of Presentation: ニューオーリンズ(アメリカ)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Crucial Role of Thrombin-Activated Fibrinolysis Inhibitor in the Pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (2016)
  • Author(s): Nobuhiro Yaoita, Kimio Satoh, Taijyu Satoh, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Masamichi Nogi, Tomohiro Otsuki, Katsuya Kozu, Kazuhiko Numano, Kota Suzuki, Shinichiro Sunamura, Shunsuke Tatebe, Tatsuo Aoki, Koichiro Sugimura, Hisanori Horiuchi, Hiroaki Shimokawa
  • Organizer: 日本循環器学会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-03-18
• [Presentation] Influence of Discontinuation of Medications after Successful Percutaneous Transluminal Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension (2016)
  • Author(s): Nobuhiro Yaoita, Koichiro Sugimura, Shunsuke Tatebe, Saori Yamamoto, Tatsuo Aoki, Masanobu Miura, Kimio Satoh, Hiroaki Shimokawa
  • Organizer: 日本循環器学会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-03-18
• [Presentation] Thrombin-activated Fibrinolysis Inhibitor in Chronic Thromboembolic Pulmonary Hypertension (2015)
  • Author(s): Nobuhiro Yaoita, Kimio Satoh, Taijyu Satoh, Koichiro Sugimura, Shunsuke Tatebe, Saori Yamamoto, Tatsuo Aoki, Masanobu Miura, Takeshi Kawamura, Hisanori Horiuchi, Yoshihiro Fukumoto, Hiroaki Shimokawa
  • Organizer: American Heart Association
  • Place of Presentation: アメリカ(オーランド)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Crucial Role of Thrombin-activated Fibrinolysis Inhibitor in the Pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (2015)
  • Author(s): Nobuhiro Yaoita, Taijyu Satoh, Kimio Satoh, Koichiro Sugimura,Shunsuke Tatebe,Saori Yamamoto,Tatsuo Aoki, Masanobu Miura, Yoshihiro Fukumoto, Hisanori Horiuchi, Hiroaki Shimokawa
  • Organizer: European Respiratory Society
  • Place of Presentation: オランダ(アムステルダム)
  • Year and Date: 2015-09-26
  • Int'l Joint Research