2015 Fiscal Year Annual Research Report
サイクロフィリンを基盤とする心血管病の成因解明と新しい診断・予防・治療法の開発
| Project/Area Number |
24390193
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| Research Institution | Tohoku University |
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Principal Investigator |
佐藤 公雄 東北大学, 高度教養教育・学生支援機構, 准教授 (80436120)
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| Co-Investigator(Kenkyū-buntansha) |
高橋 潤 東北大学, 大学病院, 講師 (00375081)
福本 義弘 久留米大学, 医学部, 教授 (70363372)
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| Project Period (FY) |
2012-04-01 – 2016-03-31
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| Keywords | 心血管疾患 / バイオマーカー / 酸化ストレス / 基礎研究の臨床応用 |
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| Outline of Annual Research Achievements |
【背景】酸化ストレスは心血管疾患発症の強力な促進因子である。これまで、酸化ストレスによりサイクロフィリンA (CyPA)が血管平滑筋細胞より分泌され、酸化ストレス増幅の悪循環に寄与することを報告した。【目的】心血管病の発症・進行における酸化ストレス分泌蛋白CyPAの役割および臨床的有用性を検討する。CyPA遺伝子改変マウスおよびその受容体欠損マウスを用い、詳細な分子学的基盤解明を行う。さらに、心血管系疾患患者由来の組織や血清を用いた発症前診断法の開発を目指す。基礎研究および臨床研究の両面から、心血管病の新しい診断・予防・治療法の開発を目指す。
【結果】CyPA遺伝子欠損マウスおよび血管平滑筋特異的過剰発現マウスを用い、大動脈瘤モデル、頚動脈内膜肥厚モデル、動脈硬化モデル、心肥大モデルでの検討を行った。いずれのモデルにおいてもCyPAは心血管疾患発症に重要であり、動脈硬化進行や大動脈瘤形成において必須蛋白であることが分かった。また、心筋梗塞患者の冠動脈硬化病変の免疫染色により、不安定プラークの病変部に強いCyPAの発現が確認された。さらに、冠動脈の狭窄病変を有する患者において、末梢血CyPA濃度が健常者に比して有意に上昇していることが確認された。この末梢血CyPA濃度は冠動脈病変の重症度に応じて有意に上昇することも確認された。【結論】CyPAは動脈硬化を促進する重要蛋白であると同時に、分泌蛋白としての特性から、新しい心血管疾患のバイオマーカーとして有用であることが示唆された。
【学会・論文報告】以上の研究成果を、国内外の学会やシンポジウムで報告し（日本循環器学会総会シンポジウム、米国心臓病学会議、欧州心臓学会議）、論文発表を行った。さらに、新しい診断薬としての可能性につき特許申請を行った。「サイクロフィリンＡによる心血管疾患の検査方法」（2012年10月30日）。
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| Research Progress Status |
27年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
27年度が最終年度であるため、記入しない。
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| Remarks |
補助事業期間延長承認日：平成27年3月20日
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[Journal Article] Basigin promotes cardiac fibrosis and failure in response to chronic pressure-overload in mice.2016
Author(s)
Suzuki K, Satoh K, Ikeda S, Sunamura S, Otsuki T, Satoh T, Kikuchi N, Omura J, Kurosawa R, Nogi M, Numano K, Sugimura K, Aoki T, Tatebe S, Miyata S, Mukherjee R, Spinale FG, Kadomatsu K, Shimokawa H.
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Journal Title
Arterioscler Thromb Vasc Biol.
Volume: 36
Pages: 636-646
DOI
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] SmgGDS as a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy and fibrosis -Novel mechanism of the pleiotropic effects of statins-2016
Author(s)
Kudo S, Satoh K, Nogi M, Suzuki K, Sunamura S, Omura J, Kikuchi N, Kurosawa R, Satoh T, Minami T, Ikeda S, Miyata S, Shimokawa H.
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Journal Title
Hypertension
Volume: 67
Pages: 878-889
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[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.
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Journal Title
Arterioscler Thromb Vasc Biol.
Volume: 36
Pages: (in press)
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[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.
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Journal Title
Circ J.
Volume: 80
Pages: 980-988
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Balloon pulmonary angioplasty improves biventricular functions and pulmonary flow in patients with chronic thromboembolic pulmonary hypertension.2016
Author(s)
Sato H, Ota H, Sugimura K, Aoki T, Tatebe S, Miura M, Yamamoto S, Yaoita N, Suzuki H, Satoh K, Takase K, Shimokawa H.
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Journal Title
Circ J.
Volume: 80
Pages: (in press)
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Rho-kinase inhibition during early cardiac development causes arrhythmogenic right ventricular cardiomyopathy in mice.2015
Author(s)
Ellawindy A, Satoh K, Sunamura S, Kikuchi N, Suzuki K, Minami T, Ikeda S, Tanaka S, Shimizu T, Enkhjargal B, Miyata S, Taguchi Y, Handoh T, Kobayashi K, Kobayashi K, Nakayama K, Miura M, Shimokawa H.
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Journal Title
Arterioscler Thromb Vasc Biol.
Volume: 35
Pages: 2172-2184
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] Selenoprotein P promotes vascular smooth muscle cell proliferation and pulmonary hypertension -A possible novel therapeutic target-（Travel Award受賞）2015
Author(s)
Kikuchi N, Satoh K, Omura J, Satoh T, Kurosawa R, Nogi M, Otsuki T , NumanoK, Kozu K, Suzuki K, Sunamura S, Tatebe S, Aoki T, Sugimura K, Shimokawa H.
Organizer
American Heart Association (AHA) Scientific Sessions
Place of Presentation
Orlando, USA
Year and Date
2015-11-08 – 2015-11-11
Int'l Joint Research
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[Presentation] Effects of PTPA on respiratory functions in patients with CTEPH.2015
Author(s)
Aoki T, Sugimura K, Tatebe S, Miura M, Yamamoto S, Yaoita N, Suzuki H, Sato H, Satoh K, Shimokawa H.
Organizer
American Heart Association (AHA) Scientific Sessions
Place of Presentation
Orlando, USA
Year and Date
2015-11-08 – 2015-11-11
Int'l Joint Research
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[Presentation] Basigin promotes cardiac fibrosis and failure in response to chronic pressure-overload in mice. （Travel Award受賞）2015
Author(s)
Suzuki K, Satoh K, Sunamura S, Omura J, Kikuchi N, Satoh T, Kurosawa R, Kudo S, Ikeda S, Otuki T, Shimokawa H.
Organizer
American Heart Association (AHA) Scientific Sessions
Place of Presentation
Orlando, USA
Year and Date
2015-11-08 – 2015-11-11
Int'l Joint Research
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[Presentation] Endothelial AMPK exerts protective effects against hypoxia-induced pulmonary hypertension in mice in vivo.2015
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, Shimokawa H.
Organizer
American Heart Association (AHA) Scientific Sessions
Place of Presentation
Orlando, USA
Year and Date
2015-11-08 – 2015-11-11
Int'l Joint Research
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[Presentation] Crucial role of thrombin activatable fibrinolysis inhibitor in the pathogenesis of chronic thromboembolic pulmonary hypertension.2015
Author(s)
Satoh T, Satoh K, Yaoita N, Kikuchi K, Omura J, Kurosawa R, Nogi M, Otsuki T, Kozu K, Numano K, Suzuki K, Sunamura S, Tatebe S, Aoki T, Sugimura K, Shimokawa H.
Organizer
American Heart Association (AHA) Scientific Sessions
Place of Presentation
Orlando, USA
Year and Date
2015-11-08 – 2015-11-11
Int'l Joint Research
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[Presentation] Plasma cyclophilin A as a useful biomarker for evaluation of the effects of percutaneous transluminal pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.2015
Author(s)
Kozu K, Satoh K, Sugimura K, Aoki T, Tatebe S, Miura M, Yamamoto S, Yaoita N, Suzuki H, Otsuki T, Sato H, Miyata S, Shimokawa H.
Organizer
American Heart Association (AHA) Scientific Sessions
Place of Presentation
Orlando, USA
Year and Date
2015-11-08 – 2015-11-11
Int'l Joint Research
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[Presentation] Selenoprotein P Promotes Vascular Smooth Muscle Cell Proliferation and Pulmonary Hypertension-A Possible Novel Therapeutic Target-2015
Author(s)
Kikuchi N, Satoh K, Omura J, Satoh T, Kurosawa R, Nogi M, Tatebe S, Aoki T, Sugimura K, Shimokawa H.
Organizer
European Society Congress (ESC) 2015
Place of Presentation
London, UK
Year and Date
2015-08-29 – 2015-09-02
Int'l Joint Research
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[Presentation] Cardiac pacemaker stimulates the brain as well as the heart in humans –A PET functional study-2015
Author(s)
Suzuki H, Satoh K, Tatebe S, Matsumoto M, Kondo M, Nakano M, Fukuda K, Hiraoka K, Tashiro M, Shimokawa H.
Organizer
European Society Congress (ESC) 2015
Place of Presentation
London, UK
Year and Date
2015-08-29 – 2015-09-02
Int'l Joint Research
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[Presentation] SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis -Novel Mechanism of the Pleiotropic Effects of Statins-2015
Author(s)
Kudo S, Satoh K, Nogi M, Suzuki K, Sunamura S, Omura J, Kikuchi N, Tanaka S, Minami T, Ikeda S, Shimokawa H.
Organizer
Scientific Session 2015 of the Arteriosclerosis, Thrombosis and Vascular Biology Council
Place of Presentation
San Francisco, USA
Year and Date
2015-05-08 – 2015-05-10
Int'l Joint Research
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[Presentation] Plasma Levels of Cyclophilin A Correlate with Circulating Inflammatory Cytokines in Patients with Pulmonary Hypertension.2015
Author(s)
Otsuki T, Satoh K, Kikuchi N, Omura J, Kudo S, Sugimura K, Aoki T, Tatebe S, Shimokawa H.
Organizer
Scientific Session 2015 of the Arteriosclerosis, Thrombosis and Vascular Biology Council
Place of Presentation
San Francisco, USA
Year and Date
2015-05-08 – 2015-05-10
Int'l Joint Research
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[Presentation] Plasma Cyclophilin A as a Useful Biomarker for Effective Percutaneous Transluminal Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension.2015
Author(s)
Satoh K, Sugimura K, Aoki T, Tatebe S, Shimizu T, Ikeda S, Yaoita N, Kudo S, Suzuki K, Omura J, Kikuchi N, Satoh T, Kurosawa R, Sunamura S, Otsuki T, Shimokawa H.
Organizer
Scientific Session 2015 of the Arteriosclerosis, Thrombosis and Vascular Biology Council
Place of Presentation
San Francisco, USA
Year and Date
2015-05-08 – 2015-05-10
Int'l Joint Research
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