Investigation of novel vasoactive agents as biomarkers for ischemic heart disease.

• Project/Area Number: 19K07900
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Hokkaido University
• Principal Investigator: SATO Kengo 北海道大学, 大学病院, 臨床検査技師 (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)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 動脈硬化 / 血管作動性物 / 虚血性心疾患 / 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 / 血管作動性物質

Outline of Research at the Start

動脈硬化に起因する虚血性心疾患は、世界第１位の死因である。虚血性心疾患や脳血管障害などの動脈硬化性疾患を予知するために、臨床では高感度CRP等が測定されてきたが、信頼に足るバイオマーカーの発見には未だ至っていないのが現状である。本研究では、動脈硬化促進作用をもつ新規血管作動性物質に対し、培養ヒト血管細胞、ApoE欠損マウスの実験、臨床データを組み合わせたトランスレーショナルリサーチを行い、最終的に虚血性心疾患のバイオマーカーを模索する。更に、未だかつてない血管細胞 (血管内皮細胞、血管平滑筋細胞、マクロファージ) を直接標的とする治療薬／診断薬の開発をし、新たな動脈硬化治療戦略の創出を目的とする。

Outline of Final Research Achievements

β-Endorphin and Lipocalin-2 promoted foam-cell formation in human macrophages. The migration was stimulated by β-Endorphin and Lipocalin-2 in human vascular smooth muscle cell. β-Endorphin and Lipocalin-2 increased THP-1 monocyte adhesion to human endothelial cells. Four-week-infusion of β-Endorphin or Lipocalin-2 into apolipoprotein E-deficient mice accelerated the development of aortic atherosclerotic lesions. In acute coronary syndrome (ACS) patients, serum β-Endorphin and Lipocalin-2 levels were increased Thus, β-Endorphin and Lipocalin-2 may become candidates for biomarker of atherosclerosis in patients with ischemic heart disease.

Academic Significance and Societal Importance of the Research Achievements

世界の死因の第1位は、動脈硬化に起因する「虚血性心疾患」である（本邦においても極めて多い）。これまで様々な対症療法が開発・施行されてきたが、本死亡数を減少させるには至っていない。本研究では、β-EndorphinおよびLipocalin-2は動脈硬化促進作用がある事を明らかにした。また、血中のβ-EndorphinおよびLipocalin-2が虚血性心疾患のバイオマーカーとなり得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] β-Endorphin mediates the development and instability of atherosclerotic plaques. (2020)
  • Author(s): Okano T, Sato K, Shirai R, Seki T, Shibata K, Koide A, Yamashita T, Hitomi T, Mori Y, Hirano T, Watanabe T.
  • Journal Title: Int J Endocrinol. Volume: 2020 Pages: 1-11
  • DOI: 10.1155/2020/4139093
  • Peer Reviewed / Open Access
• [Journal Article] Lipocalin-2 exerts pro-atherosclerotic effects as evidenced by in vitro and in vivo experiments. (2020)
  • Author(s): Shibata K, Sato K, Shirai R, Okano T, Seki T, Yamashita T, Ayaka A, Mutaumi M, Mori Y, Hirano T, Watanabe T.
  • Journal Title: Heart Vessels. Volume: 35 Issue: 7 Pages: 1012-1024
  • DOI: 10.1007/s00380-020-01556-6
  • Peer Reviewed
• [Journal Article] Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis. (2020)
  • Author(s): Watanabe T, Sato K.
  • Journal Title: Metab Cardiovasc Dis. Volume: 30 Issue: 6 Pages: 889-895
  • DOI: 10.1016/j.numecd.2020.02.017
  • Peer Reviewed
• [Journal Article] β-Endorphin mediates the development and instability of atherosclerotic plaques. (2020)
  • Author(s): Okano T, Sato K, Shirai R, Seki T, Shibata K, Yamashita T, Koide A, Tezuka T, Mori Y, Hirano T, Watanabe T.
  • Journal Title: Int J Endocrinol. Volume: 2020
  • Peer Reviewed / Open Access
• [Journal Article] Roles of the kisspeptin/GPR54 system in pathomechanisms of atherosclerosis. (2020)
  • Author(s): Watanabe T, Sato K.
  • Journal Title: Nutr Metab Cardiovasc Dis. Volume: -
  • 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] 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