Investigation of new biomarker for atherosclerosis

• Project/Area Number: 16K08943
• 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: Sato Kengo 東京薬科大学, 生命科学部, 助教 (70549930)
• Co-Investigator(Kenkyū-buntansha): 木庭 新治 昭和大学, 医学部, 教授 (20276546) ; 渡部 琢也 東京薬科大学, 生命科学部, 教授 (30297014)
• Research Collaborator: SHICHIRI Masayoshi ; MATSUYAMA Taka-aki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 動脈硬化 / 血管作動性物質 / バイオマーカー / 血管内皮細胞 / マクロファージ / 血管平滑筋細胞

Outline of Final Research Achievements

The present study provides the first evidence to demonstrate that new vasoactive agents regulate atherosclerosis. The atherosclerosis is stimulated by kisspeptin-10, but is suppressed by neopterin, chemerin-9, vaspin, and adropin. This study also shows that plasma levels of neopterin and kisspeptin-10 may become candidates for biomarker of atherosclerosis in patients with ischemic heart disease. In addition, neopterin, kisspeptin-10, adropin, vaspin, chemerin-9 and may serve as a novel therapeutic target for atherosclerosis and related diseases. Further investigations are required to develop anti-atherosclerotic drug on the basis of these agents.

Academic Significance and Societal Importance of the Research Achievements

冠動脈の動脈硬化に起因する虚血性心疾患の死亡者数は世界一である（本邦も極めて多い）。これまで様々な予防・治療が検討されてきたが、本死亡数を減少させるには至っていない。本研究では、動脈硬化に対し、キスペプチン10は促進作用が、一方、ネオプテリン、アドロピン、バスピン、ケメリン-9には抑制作用がある事を明らかにした。また、血中のネオプテリン、キスペプチン10が動脈硬化のバイオマーカーとなり得る可能性、これら新規血管作動性物質を基に動脈硬化性疾患の治療薬へ発展出来る可能性を見出した。故に、本研究は、虚血性心疾患の予防・治療に大いに貢献できると考えられる。

Research Products

• [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] 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 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] 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] A Potent Vasoconstrictor Kisspeptin-10 Induces Atherosclerotic Plaque Progression and Instability (2017)
  • Author(s): Sato K*, Shirai R*, Shinooka R, Hasegawa A, Kichise T, Koba S, Matsuyama T, Kobayashi Y, Ishibashi-Ueda H, Watanabe T.
  • Journal Title: J Am Heart Assoc Volume: 6 Issue: 4
  • DOI: 10.1161/jaha.117.005790
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Atheroprotective Effects of Tumor Necrosis Factor-Stimulated Gene-6 (2016)
  • Author(s): 2Watanabe R, Watanabe H, Takahashi Y, Kojima M, Konii H, Watanabe K, Shirai R, Sato K, Matsuyama T, Ishibashi-Ueda H, Iso Y, Koba K, Kobayashi Y, Hirano T, Watanabe T
  • Journal Title: J Am Coll Cardiol Basic Transl Sci Volume: 1 Issue: 6 Pages: 494-509
  • DOI: 10.1016/j.jacbts.2016.07.008
  • Peer Reviewed
• [Journal Article] Counteractive effects of omentin-1 against atherogenesis (2016)
  • Author(s): Watanabe K, Watanabe R, Konii H, Shirai R, Sato K, Matsuyama T, Ishibashi-Ueda H, Koba S, Kobayashi Y, Hirano T, Watanabe T
  • Journal Title: Cardiovasc Res Volume: 110 Issue: 1 Pages: 118-128
  • DOI: 10.1093/cvr/cvw016
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Facilitatory effects of fetuin-A on atherosclerosis (2016)
  • Author(s): Naito C, Hashimoto M, Watanabe K, Shirai R, Takahashi Y, Kojima M, Watanabe R, Sato K, Iso Y, Matsuyama T, Suzuki H, Ueda HI, Watanabe T
  • Journal Title: Atherosclerosis Volume: 246 Pages: 344-351
  • Peer Reviewed
• [Journal Article] Suppressive effects of glucose-dependent insulinotropic polypeptide on cardiac hypertrophy and fibrosis in angiotensin II-infused mouse models (2016)
  • Author(s): Hiromura M, Mori Y, Kohashi K, Terasaki M, Shinmura K, Negoro T, Kawashima H, Kogure M, Wachi T, Watanabe R, Sato K, Kushima H, Tomoyasu M, Nakano Y, Yamada Y, Watanabe T, Hirano T
  • Journal Title: Circ J Volume: 80 Pages: 1188-1897
  • NAID: 130005406847
  • Peer Reviewed
• [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] 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] 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, Sato K, Shibata K, Okano T, Yamashita T, Mori Y, Matsuyama T, Ishibashi-Ueda H, Hirano T, Watanabe T
  • Organizer: 第50回 日本動脈硬化学会学術集会
• [Presentation] Atherospective Effects of Tumor Necrosis Factor-Stimulated Gene-6 (2017)
  • Author(s): Watanebe R, Takahashi Y, Kojima M, Shirai M, Sato K, Watanabe T.
  • Organizer: The 66th Annual Scientific Session of the American College of Cardiology
  • Place of Presentation: Walter E Washington Convention Center (Washington, DC, USA.)
  • Year and Date: 2017-03-14
  • Int'l Joint Research
• [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] A 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: The 39th Congress of the European Society of Cardiology
  • Int'l Joint Research
• [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] Inhibitory effects of vasostatin-1 on atherosclerosis (2017)
  • Author(s): Sato Y, Watanabe R, Uchiyama N, Ozawa N, Takahashi Y, Kojima M, 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, Takahashi Y, Kojima M, Watanabe R, Sato K, Iso Y, Watanabe T.
  • Organizer: 第49回 日本動脈硬化学会学術集会
• [Presentation] Adropinの抗動脈硬化作用 (2016)
  • Author(s): 山下智之、白井玲美奈、吉澤隼巳、佐藤健吾、渡部琢也
  • Organizer: 第20回 日本心血管内分泌代謝学会学術集会
  • Place of Presentation: 東京コンベンションホール (東京都中央区)
  • Year and Date: 2016-12-16
• [Presentation] 新規植物ペプチドOsmotinの動脈硬化予防作用 (2016)
  • Author(s): 高橋由衣、渡部麗奈、小湊夏帆、小島美穂、白井玲美奈、佐藤健吾、渡部琢也
  • Organizer: 第20回 日本心血管内分泌代謝学会学術集会
  • Place of Presentation: 東京コンベンションホール (東京都中央区)
  • Year and Date: 2016-12-16
• [Presentation] Catestatinの動脈硬化抑制作用 (2016)
  • Author(s): 小島美穂、渡部麗奈、小湊夏帆、高橋由衣、佐藤健吾、森雄作、平野勉、渡部琢也
  • Organizer: 第20回 日本心血管内分泌代謝学会学術集会
  • Place of Presentation: 東京コンベンションホール (東京都中央区)
  • Year and Date: 2016-12-16
• [Presentation] Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6)の動脈硬化抑制作用 (2016)
  • Author(s): 渡部麗奈、高橋由衣、小島美穂、小湊夏帆、白井玲美奈、佐藤健吾、松山高明、木庭新治、平野勉、渡部琢也
  • Organizer: 第20回 日本心血管内分泌代謝学会学術集会
  • Place of Presentation: 東京コンベンションホール (東京都中央区)
  • Year and Date: 2016-12-16
• [Presentation] Neopterin Reacts Against Vascular Inflammation and Atherosclerosis (2016)
  • Author(s): Remina Shirai, Kengo Sato, Taka-aki Matsuyama, Shinji Koba, Watanebe R, Watanebe K, Hirano T, Takuya Watanabe
  • Organizer: The European Society of Cardiology 2016
  • Place of Presentation: Fiera di Rome (Rome, Italy)
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Preventive effects of catestatin on atherosclerosis (2016)
  • Author(s): Kojima M, Watanabe R, Watanabe K, Takahashi Y, Sato K, Mori Y, Hirano T, Watanabe T
  • Organizer: 第48回 日本動脈硬化学会学術集会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2016-07-14
• [Presentation] Preventive effects of osmotin on atherosclerosis (2016)
  • Author(s): Takahashi Y, Watanabe R, Watanabe K, Kojima M, Shirai R, Sato K, Watanabe T
  • Organizer: 第48回 日本動脈硬化学会学術集会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2016-07-14
• [Presentation] Preventive effects of chemerin on atherosclerosis (2016)
  • Author(s): Yoshizawa H, Sato K, Shirai R, Yamashita T, Matsuyama T, Koba S, Hirano T, Watanabe T.
  • Organizer: 第48回 日本動脈硬化学会学術集会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2016-07-14
• [Presentation] Counteractive Effects of Neopterin on Atherosclerosis (2016)
  • Author(s): Remina Shirai, Kengo Sato, Taka-aki Matsuyama, Shinji Koba, Watanebe R, Watanebe K, Takuya Watanabe
  • Organizer: The 65th Annual Scientific Session of the American College of Cardiology
  • Place of Presentation: McCormickPlace (Chicago, IL, USA.)
  • Year and Date: 2016-04-02
  • Int'l Joint Research