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2011 Fiscal Year Annual Research Report

血管病変におけるNotchシグナルの役割の解析と制御による血管病治療の開発

Research Project

Project/Area Number 21590950
Research InstitutionNagoya University

Principal Investigator

竹下 享典  名古屋大学, 医学部附属病院, 講師 (70444403)

Co-Investigator(Kenkyū-buntansha) 成 憲武  名古屋大学, 医学(系)研究科(研究院), 准教授 (30378228)
Keywords分子血管病態学
Research Abstract

Notchシグナルの生理作用は、発生期の臓器形成における検討で、神経発生、血管新生などの多面的作用で知られる。近年、成体においても神経組織幹細胞の維持に重要であることが発見された。しかし成体の病態におけるNotchシグナルの役割は不明な点が多い。近年我々は虚血肢の血管新生においてもNotch1受容体の活性化が重要であり、これは高脂血症治療薬スタチンで活性化できることを示した(Lab Invest 2011)。しかし、動脈硬化などの血管病におけるNotchシグナルの役割は不明であった。そこで閉塞性動脈硬化症とバージャー病の患者の病理標本において免疫組織染色を行った所、新生血管、平滑筋、炎症細胞にNotch1受容体、リガンドのJagged-1、下流の転写因子Hes-1の発現が多く認められ(Surgery Today 2013)、これらの血管病にNotchシグナルの活性化が関与していると考えられた。Notch1ヘテロ欠損マウス(全身および平滑筋特異的)の頸動脈を結紮して、血管障害による内膜増殖モデルを作製したところ、新生内膜の減少を認めた。新生内膜および培養平滑筋において、Notch1ヘテロ欠損は平滑筋の増殖、遊走能を抑制し、アポトーシス誘導に深く関わっていた(Circulation2010)。さらに動脈硬化モデルであるApolipoproteinEホモ欠損マウスにNotchシグナルを抑制するgamma-secretase阻害薬を投与したところ炎症反応浸潤が抑制され、さらに動脈硬化巣も抑制された(Biochem Biophys Res Commun 2009)。同薬剤を作用させると単離単球においてもICAM-1の発現は低下し、接着・遊走能も減弱した。このようにNotchシグナルは平滑筋、炎症細胞の機能を制御して、血管病の病態に大きく関わり、治療標的となりうると考えられた。

Current Status of Research Progress
Reason

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

  • Research Products

    (15 results)

All 2013 2011

All Journal Article (11 results) (of which Peer Reviewed: 9 results) Presentation (4 results)

  • [Journal Article] Association between cardiopulmonary exercise and dobutamine stress testing in ambulatory patients with idiopathic dilated cardiomyopathy: A comparison with peak VO(2) and VE/VCO(2) slope.2013

    • Author(s)
      Okumura T, Hirashiki A, Yamada S, Cheng XW, Takeshita K, Murohara T.
    • Journal Title

      Int J Cardiol.

      Volume: 162 Pages: 234-9

    • Peer Reviewed
  • [Journal Article] Association of cardiorespiratory fitness with characteristics of coronary plaque: Assessment using integrated backscatter intravascular ultrasound and optical coherence tomography.2013

    • Author(s)
      Yoshikawa D, Ishii H, Kurebayashi N, Sato B, Hayakawa S, Takeshita K, Amano T, Uetani T, Yamada S, Murohara T.
    • Journal Title

      Int J Cardiol.

      Volume: 162 Pages: 123-8

    • Peer Reviewed
  • [Journal Article] Inhibition of mineralocorticoid receptor is a renoprotective effect of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin.2011

    • Author(s)
      Cheng XW, Kuzuya M, Huang Z, Li P, Takeshita K, Hirashiki A, Shi GP, Okumura K, Murohara T.
    • Journal Title

      J Hypertens.

      Volume: 29(3) Pages: 542-52

    • Peer Reviewed
  • [Journal Article] Impact of the low- to high-density lipoprotein cholesterol ratio on composition of angiographically ambiguous left main coronary artery plaque.2011

    • Author(s)
      Kurebayashi N, Yoshikawa D, Ishii H, Sato B, Ando H, Takeshita K, Amano T, Murohara T.
    • Journal Title

      Circ J.

      Volume: 75(8) Pages: 1960-7

    • Peer Reviewed
  • [Journal Article] Circulating omentin is associated with coronary artery disease in men.2011

    • Author(s)
      Shibata R, Ouchi N, Kikuchi R, Takahashi R, Takeshita K, Kataoka Y, Ohashi K, Ikeda N, Kihara S, Murohara T.
    • Journal Title

      Atherosclerosis.

      Volume: 219(2) Pages: 811-4

    • Peer Reviewed
  • [Journal Article] Ankle brachial pressure index but not brachial-ankle pulse wave velocity is a strong predictor of systemic atherosclerotic morbidity and mortality in patients on maintenance hemodialysis.2011

    • Author(s)
      Tanaka M, Ishii H, Kasuga H, Takeshita K, Yoshikawa D, Amano T, Murohara T.
    • Journal Title

      Atherosclerosis.

      Volume: 219(2) Pages: 643-7

    • Peer Reviewed
  • [Journal Article] 高コレステロール治療薬(スタチン)によるNotchシグナルを介した血管新生メカニズムの解明.2011

    • Author(s)
      菊地良介, 竹下享典, 山本晃士, 松本祐之, 松下正.
    • Journal Title

      らぼ: 社団法人愛知県臨床衛生検査技師会誌

      Volume: 62(2) Pages: 9-14

  • [Journal Article] Platelet activation and induction of tissue factor in acute and chronic atrial fibrillation: involvement of mononuclear cell-platelet interaction.2011

    • Author(s)
      Hayashi M, Takeshita K, Inden Y, Ishii H, Cheng XW, Yamamoto K, Murohara T.
    • Journal Title

      Thromb Res.

      Volume: 128 Pages: e113-8

    • Peer Reviewed
  • [Journal Article] Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF.2011

    • Author(s)
      Kikuchi R, Takeshita K, Uchida Y, Kondo M, Cheng XW, Nakayama T, Yamamoto K, Matsushita T, Liao JK, Murohara T.
    • Journal Title

      Lab Invest.

      Volume: 91 Pages: 691-703

    • Peer Reviewed
  • [Journal Article] Coincidental finding of isolated congenital double-orifice mitral valve in two adult patients.2011

    • Author(s)
      Takeshita K, Inden Y, Murohara T.
    • Journal Title

      Eur J Echocardiogr

      Volume: 12 Pages: E26

    • Peer Reviewed
  • [Journal Article] 拡張型心筋症における副交感神経活性の検討.2011

    • Author(s)
      住田佳陽, 平敷安希博, 奥村貴裕, 篠田典宏, 河野裕治, 諸岡貴子, 竹下享典, 松本祐之, 山田純生, 室原豊明.
    • Journal Title

      心臓リハビリテーション

      Volume: 16 Pages: 197-201

  • [Presentation] Association of A Fat-Derived Hormone Omentin with Coronary Artery Disease in Men2011

    • Author(s)
      Rei Shibata, Noriyuki Ouchi, Ryosuke Kikuchi, Ryotaro Takahashi, Kyosuke Takeshita, Yoshiyuki Kataoka, Koji Ohashi, Nobuo Ikeda, and Toyoaki Murohara
    • Organizer
      American Heart Association
    • Place of Presentation
      Orlando (USA)
    • Year and Date
      20111112-20111116
  • [Presentation] Prognostic Value of Heart Rate Recovery Testing in Addition to Brain Natriuretic Peptide Levels in Ambulatory Patients with Nonischemic Dilated Cardiomyopathy2011

    • Author(s)
      Akihiro Hirashiki, Norihiro Shinoda, Takahiro Okumura, Yuji Kono, Xian W Cheng, Kyosuke Takeshita, Sumio Yamada, and Toyoaki Murohara
    • Organizer
      American Heart Association
    • Place of Presentation
      Orlando (USA)
    • Year and Date
      20111112-20111116
  • [Presentation] Midkine Deteriorates Atherosclerosis by its Proinflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein-E Knockout Mice2011

    • Author(s)
      Yoshio Takemoto, Mitsuru Horiba, Masahide Harada, Kyosuke Takeshita, Toyoaki Murohara, Kenji Kadomatsu, Itsuo Kodama, and Kaichiro Kamiya
    • Organizer
      American Heart Association
    • Place of Presentation
      Orlando (USA)
    • Year and Date
      20111112-20111116
  • [Presentation] Impact of Mild to Moderate Renal Dysfunction on Left Ventricular Relaxation Function and Prognosis in Ambulatory Patients with Nonischemic Dilated Cardiomyopathy2011

    • Author(s)
      Kei Ohshima, Akihiro Hirashiki, Takahiro Okumura, Kyosuke Takeshita, Xian W Cheng, Mutsuharu Hayashi, Yasuko Bando, and Toyoaki Murohara
    • Organizer
      American Heart Association
    • Place of Presentation
      Orlando (USA)
    • Year and Date
      20111112-20111116

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Published: 2014-07-24  

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