心筋梗塞の発症にかかわる血小板活性化におけるミトコンドリアの役割の研究

2011 Fiscal Year Annual Research Report

• Project/Area Number: 21590911
• Research Institution: Tokai University
• Principal Investigator: 後藤 信哉 東海大学, 医学部, 教授 (50225653)
• Keywords: 血小板 / ミトコンドリア / 血栓 / 心筋梗塞 / イメージング / カルシウム / コンピューターモ

Research Abstract

血小板細胞には核がないため、分裂、増殖することはない。血小板細胞の主要な生理機能は細胞表面の活性化受容体刺激後の活性化反応である。われわれは、ヒト血小板を採取してトロンビン受容体、ADP受容体などを選択的に刺激した前後の血小板細胞内ミトコンドリアの数、形態、局在情報を定量化した。血小板細胞刺激前後においてミトコンドリアは基本的に安定した形状を維持していることを明らかにした。細胞内のミトコンドリアの局在情報をもとに、血小板細胞基盤モデルをコンピューター上に再現した。
トロンビン、ADPなどの刺激後数分以内に完了する血小板細胞活性化反応は、細胞内シグナル蛋白リン酸化反応により仲介される。本年度の研究にて、リン酸化刺激の局在変化を明らかにするために、リン酸化vasodilator stimulated phosphoprotein(VASP)に対する特異抗体を細胞内に導入し、その局在変化をイメージングによる半定量する技術を確立した。VASPのリン酸化はATPの分解と共役する反応であるが、採取した直後の血液から分離した血小板を使用する限りにおいては、ミトコンドリア機能阻害時にVASPリン酸化阻害効果を確認することはできなかった。細胞表面の受容体刺激開始後数分以内に完了する血小板活性化反応を担うに十分量のATPの細胞内蓄積を示唆した。
平成22年度の研究において、von Willebrand因子への安定した結合はFCCP,oligomycin,antimycinなどのミトコンドリア機能阻害薬によっても阻害されないことを確認した。同時に、von Willebrand因子に結合した血小板細胞内のカルシウムイオン濃度の周期的上昇はミトコンドリア機能阻害により阻害されることを示した。平成23年度においては、さらに接着からカルシウムイオン濃度上昇までの時間経過を精緻に計測した。ミトコンドリア機能阻害時にはカルシウムイオン濃度の上昇が抑制されるのみでなく、von Willebrand因子への血小板の接着後、カルシウムイオン濃度上昇開始までの時間も延長することを示した。
ATP産生を司るミトコンドリア機能とシグナル蛋白リン酸化により仲介される活性化反応を取り込んだ血小板細胞活性化モデルを、実証実験成果により精緻化し、代謝と活性化の関連を定量化した。

Research Products

• [Journal Article] Rivaroxaban in Patients with a Recent Acute Coronary Syndrome (2012)
  • Author(s): Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM; the ATLAS ACS 2-TIMI 51 Investigators
  • Journal Title: N Engl J Med Volume: 366 Pages: 9-19
  • DOI: 10.1056/NEJMoa1112277
  • Peer Reviewed
• [Journal Article] International Longitudinal registry of patients with atrial fibrillation at risk of stroke : Global Anticoagulant Registry in the FIELD (GARFIELD) (2012)
  • Author(s): Kakkar AK, Mueller I, Bassand JP, Fitzmaurice DA, Goldhaber SZ, Goto S, Haas S, Hacke W, Lip GYH, Mantovani LG, Verheugt FWA, Jamal W, Misselwith F, Rushton-Smith S, Turpie AGG
  • Journal Title: Am Heart J Volume: 163 Pages: 13-19
  • DOI: S0002-8703(11)00696-X[pii] 10.1016/j.ahj.2011.09.011
  • Peer Reviewed
• [Journal Article] Safety and Tolerability of Atopaxar in the Treatment of Patients With Acute Coronary Syndromes (2011)
  • Author(s): O' Donoghue ML, Bhatt DL, Wiviott SD, Goodman SD, Fitzgerald DJ, Angiolillo DJ, Goto S, Montalescot G, Zeymer U, Aylward PE, Guetta V, Dudek D, Ziecina R, Contant CF, Flather MD
  • Journal Title: Circulation Volume: 123 Pages: 1843-53
  • Peer Reviewed
• [Journal Article] Randomized Trial of Atopaxar in the Treatment of Patients With Coronary Artery Disease (2011)
  • Author(s): Wiviott SD, Flather MD, O' Donoghue ML, Goto S. Fitzgerald DJ, Cura F, Aylward P, Guetta V, Dudek D, Contant CF, Angiolillo DJ, Bhatt DL
  • Journal Title: Circulation Volume: 123 Pages: 1854-63
  • Peer Reviewed
• [Journal Article] Ethnic Differences in Cardiovascular Eisks and Mortality in Atherothrombotic Disease : Insighes From the Reduction of Atherothrombosis for Continued Health (REACH) Registry (2011)
  • Author(s): Meadows T.A., Bhatt D.L., Cannon C.P., Gersh B.J., Rother J, Goto S, Liau C, Wilson P.W.F., Salette G, Smith S.C., Steg G, for the REACH Registry Investigators
  • Journal Title: Mayo Clinic Proceedings Volume: 86 Pages: 960-967
  • DOI: 86/10/960[pii] 10.4065/mcp.2011.0010
  • Peer Reviewed
• [Journal Article] Apixaban versus Warfarin in Patients with Atrial Fibrillation (2011)
  • Author(s): Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; the ARISTOTLE Committees and Investigators
  • Journal Title: N Engl J Med.2365 : 981-992, 2011 Volume: 365 Pages: 981-992
  • DOI: 10.1056/NEJMoa1107039
  • Peer Reviewed
• [Journal Article] Prospective Cohort Study of Gastrointestinal Complications and Vascular Diseases in Patients Talking Aspirin : Rationale and Design of the MAGIC Study (2011)
  • Author(s): Origasa H, Goto S, Shimada K, Uchiyama S, Okada Y, Sugano K, Hiraishi H, Uemura N, Ikeda Y, on behalf of the MAGIC Investigators
  • Journal Title: Cardiovasc Drugs Ther Volume: 25 Pages: 551-560
  • DOI: 10.1007/s10557-011-6328-2
  • Peer Reviewed
• [Journal Article] One-Year Cardiovascular Event Rates in Japanese Outpatients With Myocardial Infarction, Stroke, and Atrial Fibrillation (2011)
  • Author(s): Goto S, Ikeda Y, Shimada K, Uchiyama S, Origasa H, Kobayashi H; The J-TRACE Investigators
  • Journal Title: Circ J Volume: 75 Pages: 2598-2604
  • DOI: JST.JSTAGE/circj/CJ-11-0378[pii]
  • Peer Reviewed
• [Journal Article] A randomized, double-blind, placebo-controlled study to evaluate the effcacy and safety of rivaroxaban in subjects with acute coronary syndrome (2011)
  • Author(s): Gibson CM, Mega JL, Burton P, Goto S, Verheugt F, Bode C, Plotnikov A, Sun X, Bruns NC, Braunwald E : Rationale and design of the Anti-Xa therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51(ATLAS-ACS 2 TIMI 51) trial
  • Journal Title: American Heart Journal Volume: 161 Pages: 815-821
  • DOI: S0002-8703(11)00160-8[pii] 10.1016/j.ahj.2011.01.026
  • Peer Reviewed
• [Presentation] Use of the CHADS2 and CHA2DS2-VASC Score in Japanese Patients with Atrial Fibrillation : A sub-analysis of the Japan Thrombosis Registryfor Atrial Fibrillation, Coronary or Cerebrovascular Events (J-TRACE) (2012)
  • Author(s): Toda E, Gregory YH Lip, Shinichiro Uchiyama S, Shimada K, Origasa H, Kobayashi H, Kawamura A, Kitagawa K, Nagao T, Ikeda Y, S.Goto
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-26
• [Presentation] Inappropriate utilization of Anticoagulation in Patients With Atrial Fibrillation : The Global Anticoagulant Registry in the FIELD (GARFIELD) Registry (2012)
  • Author(s): Gregory Lip, Jean-Pierre Bassand, David Fitzmaurice, Samuel Goldhaber, Goto S, Freek Verheugt, Alexander Turpie, Iris Mueller, Sophie Rushton-Smith, Ajay Kakkar
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-26
• [Presentation] Atopaxar and Its Effects on Markers of Platelet Activation and Inflammation : Results From the LANCELOT Program (2012)
  • Author(s): Michelle L.O'Donoghue Deepak Bhatt, Marcus Flather, Goto S, Dominick Angiolillo, Shaun Goodman, Uwe Zeymer, Philip Aylward, Gilles Montalescot, Rafal Ziecina, Fang Ren, Stephen Wiviott
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-26
• [Presentation] Long-Term Risk and Prognosis of Recurrent Cardiovascular Events in the REACH Registry (2012)
  • Author(s): Christian T.Ruff, Deepak Bhatt, Erik Ohman, Kim Eagle, Mark Alberts, Peter Wilson, Ralph D'Agostino, Amarachi A, Umez-Eronini, Charles Contant, Goto S, Philippe Steg
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-26
• [Presentation] Gender Differences in Cardiovascular Risk in Diabetic and Non-DiabeticOutpatients at Risk of or with Atherothrombosis in the REACH Registry (2012)
  • Author(s): Jacob A.Udell, Annie Nguyen, Philippe Steg, Benjamin Scirica, Kim Eagle, Erik Ohman, Goto S, Kevin Crowley, Peter Wilson, Deepak Bhatt
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-25
• [Presentation] Resistant Hypertension : A Frequent And Ominous Finding Among Hypertensive Patients With Atherothrombosis (2012)
  • Author(s): Dharam J.Kumbhani, Philippe Steg, Christopher Cannon, Kim Eagle, Kevin Crowley, Goto S, Erik Ohman, George Bakris, Todd Perlstein, Scott Kinlay, Deepak Bhatt
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-25
• [Presentation] Efficacy and Safety of Apixaban Compared with Warfarin for Stroke Prevention in Atrial Fibrillation in Patients Taking Concomitant Aspirin (2012)
  • Author(s): John H.Alexander, Renato Lopes, John McMurray, Dan Atar, Daniel Wojdyla, Philip Aylward, Steen Husted, Marco Alings, Kurt Huber, Michael Hanna, Prem Pais, Basil Lewis, Goto S, Hubert Pouleur, Philippe Steg, Freek Verheugt, Christopher Granger, Lars Wallentin
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-25
• [Presentation] Metabolic Syndrome, Diabetes Mellitus, or Both and Cardiovascular Risk in Outpatients at Risk of or with Atherothrombosis in the REACH Registry (2012)
  • Author(s): Jacob A.Udell, Philippe Steg, Benjamin Scirica, Kim Eagle, Erik Ohman, Goto S, Jang Ik Cho, Peter Wilson, Deepak Bhatt
  • Organizer: ACC.12
  • Place of Presentation: McCormick Place Convention Center
  • Year and Date: 2012-03-25
• [Presentation] Long-Term Cardiovascular Outcomes in Patients with Atrial Fibrillationand Atherothrombosis in the REACH Registry (2011)
  • Author(s): Christian T Ruff, Goto S
  • Organizer: American Heart Association 2011
  • Place of Presentation: Orange County ConventionCenter
  • Year and Date: 2011-11-14
• [Presentation] 我が国における大規模臨床試験の発展に向けて (2011)
  • Author(s): 後藤信哉
  • Organizer: 第34回日本高血圧学会
  • Place of Presentation: 栃木県総合文化センター(招待講演)
  • Year and Date: 2011-10-22
• [Presentation] 薬剤溶出ステント後の抗血小板療法 (2011)
  • Author(s): 後藤信哉
  • Organizer: 第59回日本心臓病学会学術集会
  • Place of Presentation: 神戸国際会議場(招待講演)
  • Year and Date: 2011-09-23
• [Presentation] Prospective multicentre international registry of patients newly diagnosed with atrial fibrillation at risk of stroke : the Garfield registry (2011)
  • Author(s): A.K.Kakkar, Goto S
  • Organizer: ESC Congress 2011
  • Place of Presentation: Inter Continental Paris le Grand
  • Year and Date: 2011-08-27
• [Presentation] Future Perspective of Warfarin and Newer Generation of Oral Anticoagulants (2011)
  • Author(s): 後藤信哉
  • Organizer: The 75th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: パシフィコ横浜(招待講演)
  • Year and Date: 2011-08-03
• [Presentation] Lower Risk of Coronary Events in Japanese Outpatients with Ischemic Stroke-Results from the Effective Vascular Event Reduction after Stroke Registry (2011)
  • Author(s): 後藤信哉
  • Organizer: The 75th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-08-03
• [Presentation] ROLE OF MITOCHONDRIA IN THE PROCESS OF PLATELET ACTIVATION AND THROMBUS FORMATION UNDER BLOOD FLOW CONDITIONS (2011)
  • Author(s): Tamura N, Nanazawa Y, Goto S
  • Organizer: ISTH 2011 KYOTO JAPAN
  • Place of Presentation: Kyoto International Conference Center
  • Year and Date: 2011-07-28
• [Presentation] DEVELOPMENT OF PLATELET CELL SIMULATOR IMPLEMENTINGTHE FUNCTION OF RELEASE REACTION (2011)
  • Author(s): Nanazawa Y, Tamura N, Goto S, Sunaga Y Koyama T, Yokota H
  • Organizer: ISTH 2011 KYOTO JAPAN
  • Place of Presentation: Kyoto International Conference Center
  • Year and Date: 2011-07-26
• [Presentation] Risk and benefit of anti-thrombotic therapy : Still ignore the bleeding risk? (2011)
  • Author(s): Goto S
  • Organizer: ISTH 2011 KYOTO JAPAN
  • Place of Presentation: Kyoto International Conference Center(招待講演)
  • Year and Date: 2011-07-25
• [Presentation] J-ROCKET AF : THE SAFETY AND EFFICACY OF RIVAROXABAN FOR PREVENTION OF STROKE IN JAPANESE PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION (2011)
  • Author(s): Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, Izumi T, Koretsune Y
  • Organizer: ISTH 2011 KYOTO JAPAN
  • Place of Presentation: Kyoto International Conference Center
  • Year and Date: 2011-07-25
• [Presentation] 血管内治療における抗血小板薬の役割 (2011)
  • Author(s): 後藤信哉
  • Organizer: 第10回日本頸部脳血管治療学会
  • Place of Presentation: 千里ライフサイエンスセンター(招待講演)
  • Year and Date: 2011-06-11
• [Presentation] Aspirin or other antipletet for primary prevention (2011)
  • Author(s): Goto S
  • Organizer: The 1st Asia Pacific Congress on CONTROVERSIES TO CONSENSUS IN DIABETES, OBESITY AND HYPERTENSION
  • Place of Presentation: Kerry Hotel Pudong, Shanghai(招待講演)
  • Year and Date: 2011-06-04
• [Presentation] A Call to Action (2011)
  • Author(s): Goto S
  • Organizer: 18th Asia Pacific Congress of Cardiology
  • Place of Presentation: Kuala Lumpur ConventionCenter(招待講演)
  • Year and Date: 2011-05-05
• [Presentation] COMPUTER SIMULATION OF ARTERIAL THROMBUS FORMATION Atherosclerotic Plaque (2011)
  • Author(s): Goto S, Komai T, Kawahara H, Tajima S
  • Organizer: ACC.11
  • Place of Presentation: New Orleans
  • Year and Date: 2011-04-04
• [Book] 抗血栓療法ハンドブック (2011)
  • Author(s): 後藤信哉
  • Total Pages: 1-107
  • Publisher: 中外医学社
• [Book] How Can We Avoid a Stroke Crisis in the Asia-Pacific Region? Working Group Report : Stroke Prevention in Patients with Atrial Fibrillation (2011)
  • Author(s): Goto S, Hankey G, Hills MT, Hu D, Hu HH, Lip GY, MBE TL, Quek DK, Sim K-H, Tanahashi N, Tse H-F, Yoon B-W, Zhang S
  • Total Pages: 82
  • Publisher: Chameleon Communications International : 1-82, 2011
• [Book] そこが知りたい抗血栓療法 (2011)
  • Author(s): 後藤信哉
  • Total Pages: 259
  • Publisher: メディカルビュー