動脈硬化保護作用をもつ新規善玉ペプチド：虚血性心疾患の診断及び治療薬への応用

• Project/Area Number: 17K08993
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: 渡部 琢也 東京薬科大学, 生命科学部, 教授 (30297014)
• Co-Investigator(Kenkyū-buntansha): 佐藤 健吾 東京薬科大学, 生命科学部, 助教 (70549930)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Discontinued (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 動脈硬化 / ペプチド / バイオマーカー / 循環器 / 内科 / 蛋白質 / 生理活性 / 臨床

Outline of Annual Research Achievements

本研究は、植物由来の新規タンパク質であるOsmotin、並びにヒト新規ペプチドであるChemerin-9、Legumain、β-Endorphin、Lipocalin-2の動脈硬化制御作用を世界で初めて明らかにするため、細胞および動物実験の両面から検証した。
1. ヒト血管細胞を用い動脈硬化制御作用をin vitroで検証: 動脈硬化の主要現象である内皮細胞の炎症、マクロファージの泡沫化、平滑筋細胞の遊走に対して、OsmotinとChemerin-9は抑制的に働いたが、Legumain、β-Endorphin、Lipocalin-2は促進的に働いた。
2. 動脈硬化モデル動物への投与にて動脈硬化制御作用をin vivoで実証: アポE欠損マウスに浸透圧ポンプを用い4週間、OsmotinまたはChemerin-9を投与したところ、大動脈における動脈硬化病変の進展を有意に抑制できた。一方、Legumain、β-Endorphin、Lipocalin-2をそれぞれアポE欠損マウスに同様に投与したところ、大動脈における動脈硬化病変の進展を有意に促進させていた。
以上から、OsmotinおよびChemerin-9は動脈硬化に対する治療薬に有用であることが判明した。一方、Legumain、β-Endorphin、Lipocalin-2に関しては、各々の受容体拮抗薬が動脈硬化の治療に役立つと考えられた。

Research Products

• [Journal Article] Chemerin-9, a potent agonist of chemerin receptor (ChemR23), prevents atherogenesis. (2019)
  • Author(s): Sato K, Yoshizawa H, Seki T, Shirai R, Yamashita T, Okano T, Shibata K, Wakamatsu MJ, Mori Y, Morita T, Matsuyama TA, Ishibashi-Ueda H, Hirano T, Watanabe T.
  • Journal Title: Clin Sci (Lond). Volume: 133 Issue: 16 Pages: 1779-1796
  • DOI: 10.1042/cs20190336
  • Peer Reviewed
• [Journal Article] Legumain Promotes Atherosclerotic Vascular Remodeling. (2019)
  • Author(s): Ozawa N, Sato Y, Mori Y, Masuda H, Yamane M, Yamamoto Y, Shirai R, Watanabe R, Sato K, Mori Y, Hirano T, Watanabe T.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 9 Pages: 2195-2195
  • DOI: 10.3390/ijms20092195
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic properties of the new phytochemical osmotin for preventing atherosclerosis (2019)
  • Author(s): Watanabe T
  • Journal Title: Vessel Plus Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Docking simulation of Chemerin-9 and ChemR23 receptor (2019)
  • Author(s): Nobuoka K, Yamada H, Miyakawa T, Morikawa R, Watanabe T, Takasu M
  • Journal Title: Proceeding of 2020 10th International Conference on Bioscience, Biochemistry and Bioinformatics (ICBBB 2020) Volume: -
• [Journal Article] Inhibitory effects of vasostatin-1 against atherogenesis (2018)
  • Author(s): Sato Y, Watanabe R, Uchiyama N, Ozawa N, Takahashi Y, Shirai R, Sato K, Mori Y, Matsuyama T, Ishibashi-Ueda H, Hirano T, Watanabe T
  • Journal Title: Clinical Science Volume: 132 Issue: 23 Pages: 2493-2507
  • DOI: 10.1042/cs20180451
  • Peer Reviewed
• [Journal Article] Anti-atherogenic effects of vaspin on human aortic smooth muscle cell/macrophage responses and hyperlipidemic mouse plaque phenotype (2018)
  • Author(s): Sato K, Shirai R, Yamaguchi M, Yamashita T, Shibata K, Okano T, Mori Y, Matsuyama T, Ishibashi-Ueda H, Hirano T, Watanabe T
  • Journal Title: International Journal of Molecular Sciences Volume: 11 Issue: 6 Pages: 19-19
  • DOI: 10.3390/ijms19061732
  • Peer Reviewed / Open Access
• [Journal Article] A dipeptidyl peptidase-4 inhibitor suppresses macrophage foam cell formation in diabetic db/db mice and type 2 diabetes patients (2018)
  • Author(s): Terasaki M, Hiromura M, Mori Y, Kohashi K, Kushima H, Koshibu M, Saito T, Yashima H, Watanabe T, Hirano T
  • Journal Title: International Journal of Endocrinology Volume: 2018 Pages: 8458304-8458304
  • DOI: 10.1155/2018/8458304
  • Peer Reviewed / Open Access
• [Journal Article] Emerging roles of cardiotrophin-1 in the pathogenesis and biomarker of atherosclerosis (2018)
  • Author(s): Watanabe T, Konii H, Sato K
  • Journal Title: J-Open Access Journal of Multidisciplinary Science Volume: 1 Issue: 1 Pages: 94-105
  • DOI: 10.3390/j1010010
  • Peer Reviewed / Open Access
• [Journal Article] Novel phytopeptide osmotin mimics preventive effects of adiponectin on vascular inflammation and atherosclerosis (2018)
  • Author(s): Takahashi Y, Watanabe R, Sato Y, Ozawa N, Kojima M, Watanabe-Kominato K, Shirai R, Sato K, Hirano T, Watanabe T
  • Journal Title: Metabolism Volume: 83 Pages: 128-138
  • DOI: 10.1016/j.metabol.2018.01.010
  • Peer Reviewed
• [Journal Article] Catestatin prevents macrophage-driven atherosclerosis but not arterial injury-induced neointimal hyperplasia (2018)
  • Author(s): Kojima M, Ozawa N, Mori Y, Takahashi Y, Watanabe-Kominato K, Shirai R, Watanabe R, Sato K, Matsuyama T, Ishibashi-Ueda H, Koba S, Kobayashi Y, Hirano T, Watanabe T
  • Journal Title: Thromb Haemost Volume: 118 Issue: 01 Pages: 182-194
  • DOI: 10.1160/th17-05-0349
  • Peer Reviewed
• [Journal Article] Adropin contributes to anti-atherosclerosis by suppressing monocyte-endothelial cell adhesion and smooth muscle cell proliferation (2018)
  • Author(s): Sato K, Yamashita T, Shirai R, Shibata K, Okano T, Yamaguchi M, Mori Y, Matsuyama T, Ishibashi-Ueda H, Hirano T, Watanabe T
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 5 Pages: 1293-1293
  • DOI: 10.3390/ijms19051293
  • Peer Reviewed / Open Access
• [Journal Article] Emerging roles of tumor necrosis factor-stimulated gene-6 in the pathophysiology and treatment of atherosclerosis (2018)
  • Author(s): Watanabe R, Sato Y, Ozawa N, Takahashi Y, Koba S, Watanabe T
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 2 Pages: 465-465
  • DOI: 10.3390/ijms19020465
  • Peer Reviewed / Open Access
• [Journal Article] Neopterin Counters Vascular Inflammation and Atherosclerosis (2017)
  • Author(s): Shirai R, Sato K, Yamashita T, Yamaguchi M, Okano T, Watanabe-Kominato K, Rena Watanabe R, Matsuyama T, Ishibashi-Ueda H, Koba S, Kobayashi Y, Hirano T, Watanabe T
  • Journal Title: J Am Heart Assoc Volume: 7 Issue: 3
  • DOI: 10.1161/jaha.117.007359
  • Peer Reviewed / Open Access
• [Journal Article] Adipose tissue-derived omentin-1 function and regulation (2017)
  • Author(s): Watanabe T, Watanabe-Kominato K, Takahashi Y, Kojima M, Watanabe R
  • Journal Title: Compr Physiol Volume: 7 Pages: 765-781
  • DOI: 10.1002/cphy.c160043
  • Peer Reviewed
• [Presentation] Docking simulation of Chemerin-9 and ChemR23 receptor (2020)
  • Author(s): Nobuoka K, Yamada H, Miyakawa T, Morikawa R, Watanabe T, Takasu M
  • Organizer: 2020 10th International Conference on Bioscience, Biochemistry and Bioinformatics (ICBBB 2020)
  • Int'l Joint Research
• [Presentation] 動脈硬化は生命を脅かす怖い病気 (2019)
  • Author(s): 渡部琢也
  • Organizer: たちかわ市民交流大学講座
  • Invited
• [Presentation] Anti-atherogenic effects of vaspin on human aortic smooth muscle cell/macrophage responses and hyperlipidemic mouse plaque phenotype (2018)
  • Author(s): Shirai R, Yamaguchi M, Yamashita T, Shibata K, Okano T, Sato K, Watanabe T
  • Organizer: 第50回 日本動脈硬化学会学術集会
• [Presentation] Vasostatin-1の動脈硬化抑制作用 (2018)
  • Author(s): 佐藤裕希、内山のぞみ、小澤奈菜、白井玲美奈、佐藤健吾、渡部琢也
  • Organizer: 第7回 医薬工３大学包括連携推進シンポジウム
• [Presentation] 血管炎症と動脈硬化に対するNeopterinの抑制作用 (2018)
  • Author(s): 白井玲美奈、佐藤健吾、松山高明、木庭新治、平野勉、植田初江、渡部琢也
  • Organizer: 東京薬科大学生命科学部 25周年記念シンポジウム
• [Presentation] 新規ペプチドVasostatin-1の動脈硬化抑制作用 (2018)
  • Author(s): 佐藤裕希、内山のぞみ、小澤奈菜、白井玲美奈、佐藤健吾、渡部琢也
  • Organizer: 第10回 大学コンソーシアム八王子学生発表会
• [Presentation] Novel phytopeptide osmotin mimics atheroprotective effects of adiponectin via AdipoR1 (2017)
  • Author(s): Takahashi Y, Watanabe R, Sato Y, Ozawa N, Shirai R, Sato K, Watanabe T
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Potent vasoconstrictor kisspeptin-10 induces atherosclerotic plaque progression and instability: reversal by its receptor GPR54 antagonist (2017)
  • Author(s): Sato K, Shirai R, Yamashita T, Yoshizawa H, Watanabe R, Matsuyama T, Ishibashi-Ueda H, Koba S, Kobayashi Y, Hirano T, Watanabe T
  • Organizer: 39th Congress of the European Society of Cardiology
  • Int'l Joint Research
• [Presentation] Atheroprotective effects of tumor necrosis factor-stimulated gene-6 (2017)
  • Author(s): Watanabe R, Takahashi Y, Shirai R, Sato K, Watanabe T
  • Organizer: 66th Annual Scientific Sessions of the American College of Cardiology
  • Int'l Joint Research
• [Presentation] Inhibitory effects of vasostatin-1 on atherosclerosis (2017)
  • Author(s): Sato Y, Watanabe R, Uchiyama N, Takahashi Y, Watanabe T
  • Organizer: 第49回 日本動脈硬化学会学術集会
• [Presentation] Preventive effects of adropin on atherosclerosis (2017)
  • Author(s): Yamashita T, Shirai R, Yoshizawa H, Sato K, Watanabe T
  • Organizer: 第49回 日本動脈硬化学会学術集会
• [Presentation] Facilitatory effects of fetuin-A on atherosclerosis (2017)
  • Author(s): Shirai R, Naito C, Hashimoto M, Iso Y, Watanabe T
  • Organizer: 第49回 日本動脈硬化学会学術集会