Novel therapeutic strategy for atherosclerosis by regulating myeloid lineage cells in socially defeated mice

• Project/Area Number: 15K09162
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• 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), 講師 (00240036)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: うつ病 / 動脈硬化 / 好中球細胞外トラップ

Outline of Final Research Achievements

Depression is an independent risk factor of cardiovascular disease (CVD); however, the causal association remains undefined. We exposed mice to repeated social defeat (RSD) to precipitate depressive-like behaviors, and investigated the effects on atherosclerosis. Defeated mice showed higher increase in atherosclerotic lesion areas in the aortic root and entire aorta than control mice. While Ly-6G- and Mac3-positive areas in the aortic root were comparable between the groups, citrullinated histone H3 (Cit-H3)- and myeloperoxidase (MPO)-positive areas, markers of neutrophil extracellular traps (NETs), were significantly increased in the defeated mice. Treatment with DNase I completely diminished the exaggerated atherosclerosis. Our findings demonstrate that exposure to RSD promotes atherosclerosis by augmenting NETs formation within the plaque. This provides new insight into the underlying mechanism of depression-related CVD.

Research Products

• [Journal Article] Augmented neutrophil extracellular traps formation promotes atherosclerosis development in socially defeated apoE-/- mice (2018)
  • Author(s): Keita Yamamoto, Hiroyuki Yamada, Noriyuki Wakana, Masakazu Kikai, Kensuke Terada, Naotoshi Wada, Shinichiro Motoyama, Makoto Saburi, Takeshi Sugimoto, Daisuke Kami, Takehiro Ogata, Masakazu Ibi, Chihiro Yabe-Nishimura, Satoaki Matoba
  • Journal Title: Biochemical and Biophysical Research Communications Volume: xxx Pages: 1-7
  • Peer Reviewed / Open Access
• [Journal Article] Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE-/- mice (2018)
  • Author(s): Masakazu Kikai, Hiroyuki Yamada, Noriyuki Wakana, Kensuke Terada, Keita Yamamoto, Naotoshi Wada, Shinichiro Motoyama, Makoto Saburi, Takeshi Sugimoto, Daisuke Irie, Taku Kato, Hiroyuki Kawahito, Takehiro Ogata, Satoaki Matoba
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 497 Pages: 1097-1103
  • Peer Reviewed / Open Access
• [Journal Article] Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm (2017)
  • Author(s): Kotaro Miyagawa, Takehiro Ogata, Tomomi Ueyama, Takeru Kasahara, Naohiko Nakanishi, Daisuke Naito, Takuya Taniguchi, Tetsuro Hamaoka, Naoki Maruyama, Masahiro Nishi, Taizo Kimura, Hiroyuki Yamada, Hiroki Aoki, Satoaki Matoba
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 487 Pages: 587-593
  • Peer Reviewed / Open Access
• [Journal Article] Dipeptidyl peptidase-4 inhibitor sitagliptin improves pancreatic β-cell function in hypertensive diabetic patients treated with angiotensin receptor blockers. (2015)
  • Author(s): Fukui K, Kawahito H, Wakana N, Kikai M, Terada K, Yamamoto K, Irie D, Kato T, Miyagawa S, Yamada H.
  • Journal Title: J Renin Angiotensin Aldosterone Syst. Volume: １６ Issue: 4 Pages: 1001-1009
  • DOI: 10.1177/1470320315587180
  • Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Short-Term Treatment with an Angiotensin II Receptor Blocker Prevents Necrotic Core Formation by Inhibiting Oxidative Stress-Mediated Apoptosis in Macrophages. (2015)
  • Author(s): Kishida S, Yamada H, Wakana N, Kawahito H, Irie D, Kato T, Kikai M, Terada K, Yamamoto K, Wada N, Motoyama S, Takata H, Yokoi H, Tsubakimoto Y, Ogata T, Ueyama T, Satoaki M.
  • Journal Title: Int J Cardiovasc Res Volume: ５ Issue: 01 Pages: 1-1
  • DOI: 10.4172/2324-8602.1000252
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Repeated social defeat enhances neutrophil extracellular traps formation in vivo and in vitro: Potential implication in the exaggerated atherosclerosis in chronic social stress-exposed apoE-/- mice. (2017)
  • Author(s): 36.Yamamoto K, Yamada H, Terada K, Motoyama S, Wada N, Saburi M, Kikai M, Wakana N, Matoba S.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Place of Presentation: New Orleans
  • Year and Date: 2017-11-15
  • Int'l Joint Research
• [Presentation] Augmented neutrophil extracellular traps formation promotes atherosclerosis development in socially defeated apoE-/- mice. (2017)
  • Author(s): Yamamoto K, Yamada H, Terada K, Motoyama S, Wada N, Saburi M, Sugimoto T, Kikai M, Wakana N, Matoba S.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research
• [Presentation] Repeated psychosocial stress enhances neutrophil elastase activity in adipose tissue: Possible mechanisms of highly vulnerable to diet-induced insulin resistance. (2017)
  • Author(s): Motoyama S, Yamada H, Yamamoto K, Terada K, Wada N, Saburi M, Sugimoto T, Kikai M, Wakana N, Matoba S.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research
• [Presentation] Maternal high-fat diet promotes palmitate-induced inflammasome activation of bone marrow derived macrophages from adult offspring: Possible mechanisms of increased susceptibility to insulin resistance. (2017)
  • Author(s): Wada N, Yamada H, Motoyama S, Yamamoto K, Terada K, Saburi M, Sugimoto T, Kikai M, Wakana N, Matoba S.
  • Organizer: American Heart Association (米国心臓病学術会議)
  • Int'l Joint Research
• [Presentation] Transplantation of brown adipose tissue inhibits atherosclerosis in apoE deficient mice via activation of FGF-21/adiponectin axis. (2015)
  • Author(s): Kikai M, Terada K, Yamamoto K, Motoyama S, Wada N, Wakana N, Yamada H.
  • Organizer: 米国心臓病学術会議
  • Place of Presentation: オーランド(USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research