Elucidation of intrinsic fibrinolytic activities potentiated vascular endothelial cells and its possibility in prophylaxis of thrombotic disease

• Project/Area Number: 25461123
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Suzuki Yuko 浜松医科大学, 医学部, 准教授 (20345812)
• Co-Investigator(Kenkyū-buntansha): URANO TETSUMEI 浜松医科大学, 医学部, 教授 (50193967) ; SANO HIDETO 浜松医科大学, 医学部, 助教 (80623842)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 血管内皮細胞 / 線溶活性 / 組織型プラスミノゲンアクチベータ / リアルタイムイメージング解析 / 蛍光顕微鏡 / tenecteplase / 流れずり応力 / 組織型プラスミノゲンアクチベーター / 定量解析 / 可視化解析 / 糖鎖

Outline of Final Research Achievements

Vascular endothelial cells (VECs) play essential role in keeping the fluidity of circulating blood by expressing dynamic antithrombotic effects. Tissue-type plasminogen activator (tPA) secreted from VECs is a key molecule for initiating fibrinolytic, and retained on the cell surface after secretion. Cell surface-retained tPA effectively evokes both plasminogen activation and fibrin clot dissolution (fibrinolysis) on VECs. Our quantitative assessment of these two different plasminogen activator activities contributes to identify the unique characteristics of TNK-tPA (tenecteplase) having lower affinity to VEC surface compared to wild-type (alteplase).

Research Products

• [Journal Article] Activities of wild-type and variant tissue-type plasminogen activators retained on vascular endothelial cells (2016)
  • Author(s): Suzuki Y, Sano H, Tomczyk M, Brzoska T and Urano T
  • Journal Title: FEBS Open Bio Volume: 6 Issue: 5 Pages: 469-476
  • DOI: 10.1002/2211-5463.12057
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 線溶系の最新情報と今後の展望 (2016)
  • Author(s): 浦野哲盟、鈴木優子
  • Journal Title: 臨床血液 Volume: 57 Pages: 333-339
  • NAID: 130005145473
• [Journal Article] Endogenously Generated Plasmin at the Vascular Wall Injury Site Amplifies Lysine Binding Site-Dependent Plasminogen Accumulation in Microthrombi. (2015)
  • Author(s): Brzoska T, Tanaka-Murakami A, Suzuki Y, Sano H, Kanayama N, Urano T.
  • Journal Title: PLoSONE Volume: 10 Issue: 3 Pages: 1371-1371
  • DOI: 10.1371/journal.pone.0122196
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 凝固線溶系分子による血管内皮細胞機能の維持 (2014)
  • Author(s): 鈴木優子、浦野哲盟
  • Journal Title: 血液内科 Volume: 69 Pages: 336-342
• [Journal Article] 凝固・線溶系のしくみと血栓形成機序 血栓・塞栓症 ―治療・予防の最新動向― (2014)
  • Author(s): 浦野哲盟、鈴木優子
  • Journal Title: 日本臨床 Volume: 72 Pages: 1198-1205
• [Journal Article] 凝固線溶系 プラスミノゲンレセプター (2014)
  • Author(s): 浦野哲盟、鈴木優子
  • Journal Title: Annual Review 血液 Volume: 2014 Pages: 209-215
• [Journal Article] TM5275prolongs secreted tissue plasminogen activator retention and enhancesfibrinolysis on vascular endothelial cells. (2013)
  • Author(s): Yasui H, Suzuki Y, Sano H, Suda T, Chida K, Dan T, Miyata T, Urano T
  • Journal Title: Thromb Res Volume: ## Issue: 1 Pages: 100-105
  • DOI: 10.1016/j.thromres.2013.04.003
  • Peer Reviewed
• [Journal Article] 動脈硬化、血栓性疾患発症予防におけるスタチンの特赦な位置付け (2013)
  • Author(s): 鈴木優子、浦野哲盟
  • Journal Title: 動脈硬化予防 Volume: 12 Pages: 56-63
• [Journal Article] 血液凝固における血管内皮細胞とRASの役割 (2013)
  • Author(s): 鈴木優子、浦野哲盟
  • Journal Title: Angiotensin Research Volume: 11 Pages: 1-6
• [Presentation] Real-time imaging analysis of membrane surface-triggered fibrinolysis on vascular endothelial cells and activated platelets (2016)
  • Author(s): 鈴木優子、Brzoska Tomasz，田中宏樹、佐野秀人、浦野哲盟
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] Evaluation of activities of tissue-type plasminogen activators expressed and retained on vascular endothelial cells (2016)
  • Author(s): 鈴木優子、佐野秀人、田中宏樹、浦野哲盟
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-22
• [Presentation] 血管内皮細胞によるプラスミノゲンアクチベータ活性発現調節のリアルタイムイメージング解析 (2015)
  • Author(s): 鈴木優子、佐野秀人、田中宏樹、Brzoska Tomasz、浦野哲盟
  • Organizer: 第23回日本血管生物医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-10
• [Presentation] 血管内皮の抗血栓機能のリアルタイムイメージング解析 (2015)
  • Author(s): 鈴木優子
  • Organizer: 第20回静岡健康・長寿学術フォーラム
  • Place of Presentation: 静岡
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] 血管内皮細胞表面におけるプラスミノゲンアクチベーター活性の評価 (2015)
  • Author(s): 鈴木優子、佐野秀人、Tomczyk Martyna、Brzoska Tomasz、浦野哲盟
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] 血管内皮細胞発現tPAによるプラスミン産生ならびに線溶の定量評価と変異型tPAの機能解析 (2015)
  • Author(s): 鈴木優子、Brzoska Tomasz、佐野秀人、浦野哲盟
  • Organizer: 第37回日本血栓止血学会学術集会
  • Place of Presentation: 甲府
  • Year and Date: 2015-05-21
• [Presentation] Assessment of plasminogen activator activity on vascular endothelial cells (2015)
  • Author(s): 鈴木優子
  • Organizer: The 9th Aso International Meeting
  • Place of Presentation: 南阿蘇
  • Year and Date: 2015-05-14
  • Int'l Joint Research
• [Presentation] Regulatory mechanism of fibrinolytic activity in plasma and on vascular endotherial cells(VECS):messages from congenital deficiency cases of plasminogen activator inhibitor Type1(PAI-1) in human (2014)
  • Author(s): Urano T, Suzuki Y, Sano H, Iwaki T.
  • Organizer: The 8th Congress of Asia Pacific Society of Thrombosis and Hemostasis
  • Place of Presentation: Hanoi
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Generation and differentiation of inducible pluripotent stem(IPS)cells derived from plasminogen activator inhibitor-1 deficient patient. (2014)
  • Author(s): Sano Hideto, Otsu Makoto, Iwaki Takayuki, Nagahashi Kotomi, Suzuki Yuko, Kanayama Naohiro, Urano Tetsumei
  • Organizer: 22ND International Congress On Fibrinolysis ＆ Proteolysis
  • Place of Presentation: Marseille
  • Year and Date: 2014-07-06 – 2014-07-09
• [Presentation] Visualizing plasmin on cell surfaces (2014)
  • Author(s): Urano T, Suzuki Y
  • Organizer: 60th Annual Meeting of Scientific & Standardization Committee of the ISTH
  • Place of Presentation: Milwaukee
  • Year and Date: 2014-06-25
• [Presentation] リアルタイムイメージイングによる修飾tPAの分泌動態解析 (2014)
  • Author(s): 鈴木優子 佐野秀人、Tomasz Brzoska、浦野哲盟
  • Organizer: 第36回日本血栓止血学会学術集会
  • Place of Presentation: 大坂
  • Year and Date: 2014-05-30 – 2014-05-31
• [Presentation] Generation of inducible pluripotent stem(iPS)cells from plasminogen activator inhibitor-1 deficient patient and differetiation into endothelial cells (2014)
  • Author(s): Hideto Sano, Makoto Otsu, Takayuki Iwaki, Kotomi Nagahashi,Yuko Suzuki, Naohiro Kanayama, Tetsumei Urano
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Phosphatidylserine exposure on platelets'surface requires the binding to a rigid fibrin scaffold (2014)
  • Author(s): Tomasz Brzoska, Yuko Suzuki, Hideto Sano, Tetsumei Urano
  • Organizer: The 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Visualization of secretory dynamics of tissue-type plasminogen activator and cell surface-associated fibrinolytic activity on vascular endothelial cells
  • Author(s): Suzuki Y
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島大学
  • Invited
• [Presentation] Post exocytotic- and cell surface retained- tissue plasminogen activator efficiently initiates fibrin clot lysis on vascular endothelial cells
  • Author(s): Suzuki Y
  • Organizer: 第8回 Aso International Meeting (AIM)
  • Place of Presentation: 阿蘇
• [Book] 新・血栓止血血管学「抗凝固と線溶」 (2015)
  • Author(s): 鈴木優子、他 多数
  • Total Pages: 133
  • Publisher: 金芳堂
• [Book] 日本血栓止血学会用語集web版 (2015)
  • Author(s): 鈴木優子、他 多数
  • Publisher: 日本血栓止血学会
• [Book] 血栓止血ハンドブック (2015)
  • Author(s): 鈴木重統、松野一彦、後藤信哉
  • Total Pages: 422
  • Publisher: 西村書店
• [Patent(Industrial Property Rights)] plasminogen activator inhibitor type 1 の Gly397 近傍を標的とした活性阻害分子の発明 (2014)
  • Inventor(s): 浦野哲盟、岩城孝行、鈴木優子、梅村和夫
  • Industrial Property Rights Holder: 国立大学法人浜松医科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-02-06