Novel therapeutic strategy for arterial thrombosis by targeting neutrophil extracellular trap formation in socially defeated mice

• Project/Area Number: 18K08081
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Yamada Hiroyuki 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (00240036)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 好中球 / 好中球細胞外トラップ / うつ病 / 心血管病 / 血栓形成 / 鬱病 / 血栓 / 細胞外トラップ形成 / 血小板 / 動脈硬化

Outline of Final Research Achievements

We investigated the impact of repeated social defeat (RSD) on arterial thrombosis in mice. Carotid arterial thrombosis was induced by FeCl3 application. The volume of occlusive thrombi was comparable between the defeated and control mice; however, fibrinogen/fibrin-positive areas was significantly increased in defeated mice. Further, Ly-6G-positive cells in defeated mice were co-localized with neutrophil elastase, Cit-H3, and CD42b-positive staining, suggesting that neutrophil extracellular traps (NETs) formation was enhanced in defeated mice. Treatment with DNase I completely diminished the exaggerated fibrin-rich clot formation in defeated mice. In vitro NETs formation assessed by Cit-H3/MPO double-positive cells was significantly higher in neutrophils of defeated mice. Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NETs formation, suggesting that NETosis could be a new therapeutic target in depression-related CVD development.

Academic Significance and Societal Importance of the Research Achievements

鬱病は心血管病発症の独立した危険因子であることが明らかとなってきたが、その機序は十分解明されていない。申請者らのグループは以前、鬱病モデルマウスにおいて惹起された骨髄由来免疫抑制細胞が、好中球細胞外トラップ形成（NETs）形成を介して動脈硬化形成促進に作用することを初めて報告したが、鬱病における心血管病発症機序を直接解析した報告はない。今回、鬱病モデルマウスを用いて「動脈血栓形成モデル」を作製し、NETs形成が動脈血栓形成に直接関与することを明らかにした。心血管病予防の新たな治療標的に発展させる可能性を示した点において意義深いと考える。

Research Products

• [Journal Article] Transplantation of periaortic adipose tissue inhibits atherosclerosis in apoE-/- mice by evoking TGF-β1-mediated anti-inflammatory response in transplanted graft. (2018)
  • Author(s): Terada K, Yamada H, Kikai M, Wakana N, Yamamoto K, Wada N, Motoyama S, Saburi M, Sugimoto T, Irie D, Kato T, Kawahito H, Kami D, Ogata T, Matoba S.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 501 Issue: 1 Pages: 145-151
  • DOI: 10.1016/j.bbrc.2018.04.196
  • Peer Reviewed / Open Access
• [Presentation] Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis mice model by enhancing NETs formation. (2021)
  • Author(s): Sugimoto T, Yamada H, et al.
  • Organizer: 第85回日本循環器学会
• [Presentation] Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis mouse model by enhancing NETs formation via modulation of neutrophil functional properties (2020)
  • Author(s): Sugimoto T, Yamada H, et al.
  • Organizer: European Society of Cardiology
  • Int'l Joint Research
• [Presentation] Repeated social defeat exaggerates fibrin-rich clot formation by enhancing NETs formation via platelet-neutrophil interactions (2020)
  • Author(s): Sugimoto T, Yamada H, et al.
  • Organizer: American Heart Association
  • Int'l Joint Research
• [Presentation] Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis mice model by enhancing NETs formation. (2019)
  • Author(s): Sugimoto T, Yamada H, Kubota H, Miyawaki D, Motoyama S, Wada N, Saburi M, Wakana N, Matoba S.
  • Organizer: 欧州心臓病学術会議
  • Int'l Joint Research
• [Presentation] Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis mice model by enhancing NETs formation. (2019)
  • Author(s): Sugimoto T, Yamada H, Kubota H, Miyawaki D, Saburi M, Wakana N, Matoba S.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research
• [Presentation] Repeated social defeat exaggerates fibrin-rich clot formation in FeCl3-induced arterial thrombosis model: Potential mechanisms of depression-related CVD development. (2019)
  • Author(s): Sugimoto T, Yamada H, Yamamoto K, Kubota H, Miyawaki D, Motoyama S, Wada N, Saburi M, Wakana N, Matoba S.
  • Organizer: 第83回日本循環器学会
• [Presentation] Maternal high-fat diet promotes the expansion of abdominal aortic aneurysm in adult offspring by skewing of macrophage differentiation toward osteoclast-like macrophages. (2018)
  • Author(s): Makoto Saburi, Hiroyuki Yamada, Naotoshi Wada, Shinichiro Motoyama, Takeshi Sugimoto, Hiroshi Kubota, Daisuke Miyawaki, Noriyuki Wakana, Satoaki Matoba.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research
• [Presentation] Psychological stress increases the vulnerability to high-fat diet-induced insulin resistance by enhancing neutrophil elastase activity in adipose tissue. (2018)
  • Author(s): Shinichiro Motoyama, Hiroyuki Yamada, Naotoshi Wada, Makoto Saburi, Takeshi Sugimoto, Hiroshi Kubota, Daisuke Miyawaki, Noriyuki Wakana, Satoaki Matoba.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research
• [Presentation] Maternal high-fat diet exaggerates the development of diet-induced insulin resistance in adult offspring by enhancing NLRP3 inflammasome activation. (2018)
  • Author(s): Naotoshi Wada, Hiroyuki Yamada, Shinichiro Motoyama, Makoto Saburi, Takeshi Sugimoto, Daisuke Miyawaki, Hiroshi Kubota, Noriyuki Wakana, Satoaki Matoba.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research