Crucial role of WFS1 in preventing arteriosclerosis acceleration via inhibits biological stress response and mitochondrial dynamics deterioration

• Project/Area Number: 16K09774
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tohoku University
• Principal Investigator: gao junhong 東北大学, 学際科学フロンティア研究所, 助教 (70455781)
• Co-Investigator(Kenkyū-buntansha): 宇野 健司 帝京大学, 医学部, 准教授 (50596632) ; 澤田 正二郎 東北大学, 大学病院, 講師 (60509420)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 小胞体ストレス / 動脈硬化 / 小胞体ストレス WFS1 / 炎症性内膜肥厚、動脈硬化 / macrophage / ミトコンドリア / メタボリクシンドローム

Outline of Final Research Achievements

In this study, we investigated the role of WFS1 in vascular cell biology. The WFS1 deficient mice were used to examine the effects of WFS1 on arteriosclerosis. WFS1 deficiency increased cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Bone marrow transplantation experiments revealed that donor WFS1 deficiency plays a major role in enhanced neointimal formation after cuff injury and WFS1 expressed in both hematopoietic cells and vascular cells, and contributes to protect the atherosclerotic plaque formation induced by hypercholesterolemia. Transmission electron microscopy scanning showed WFS1 deficiency increased mitochondrial morphology change.

Academic Significance and Societal Importance of the Research Achievements

食生活の欧米化や運動不足に伴い、糖尿病・高脂血症・高血圧などの代謝異常に伴って動脈硬化性疾患の増加が社会的問題となっている。動脈硬化の発症・進展には、代謝異常や喫煙などの動脈硬化の危険因子の下流で生体内ストレス応答が重要である。
動脈硬化の分子メカニズムに関する研究の中で、血管における小胞体、炎症、酸化ストレス反応及びミトコンドリア機能の関連におけるWFS1の役割についてまだ報告されてない。本研究では遺伝子改変マウスに対して複数の負荷を行うことやex vivo 、in vitroの実験系を組み合わせることで血管における生体内ストレス応答と細胞内ミトコンドリア機能の相互作用について解析を行った。

Research Products

• [Journal Article] Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation (2018)
  • Author(s): Tomohito Izumi, Junta Imai,Junpei Yamamoto,Yohei Kawana, Akira Endo,Hiroto Sugawara, Masato Kohata,Yoichiro Asai,Kei Takahashi, Shinjiro Kodama, Keizo Kaneko,Junhong Gao,Kenji Uno,Shojiro Sawada,Vladimir V. Kalinichenko, Yasushi Ishigaki, Tetsuya Yamada,1 Hideki Katagiri
  • Journal Title: Nature communications Volume: 13;9(1) Pages: 1-13
  • Peer Reviewed / Open Access
• [Journal Article] Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers (2018)
  • Author(s): Midori Honma, Shojiro Sawada,Yoshiyuki Ueno, Keigo Murakami, Tetsuya Yamada, Junhong Gao,Shinjiro Kodama, Tomohito Izumi,Kei Takahashi, Sohei Tsukita, Kenji Uno, Junta Imai, Eiji Kakazu, Yasuteru Kondo, Kei Mizuno,Naoki Kawagishi, Tooru Shimosegawa, and Hideki Katagiri
  • Journal Title: International Journal of Obesity Volume: 42(9) Pages: 1544-1555
  • Peer Reviewed / Open Access
• [Journal Article] ES Stress Protein CHOP Mediates Insulin Resistanse by Modulating Adipose Tissue Macrophage Polarity. (2017)
  • Author(s): Suzuki T, Gao J, Ishigaki Y, Kondo K, Sawada S, Izumi T, Uno K, Kaneko K, Tsukita S, Takahashi K, Asao A, Ishii N, Imai J, Yamada T, Oyadomarai S, Katagiri H
  • Journal Title: Cell Rep Volume: 18 Issue: 8 Pages: 2045-2057
  • DOI: 10.1016/j.celrep.2017.01.076
  • Peer Reviewed / Open Access