Elucidation of a new mechanism involved in the pathogenesis of atherosclerosis based on the oxLDL kinetic imaging

• Project/Area Number: 15K01309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biomedical engineering/Biomaterial science and engineering
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Nakano Atsushi 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (90217787)
• Project Period (FY): 2015-04-01 – 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 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 動脈硬化 / 骨格筋 / 褐色脂肪 / 酸化LDL / 運動負荷 / バイオイメージング / 褐色脂肪細胞 / nanoSPECT

Outline of Final Research Achievements

The whole-body imaging studies were performed using several strains of oxLDL receptor KO mice. We found that oxLDL accumulation to brown adipocyte tissues, skeletal muscle and other organs except the liver and spleen became completely disappeared in one strain. In contrast, the accumulation to liver and spleen were nearly doubled to compared to the WT mice.
Increased clearance associated with activation of brown adipocyte tissue or skeletal muscle were observed.
In addition, we studied the relationship between exercise load and arteriosclerosis with this receptor. The exercise group had a healthy long life; however, it was observed larger area of atherosclerosis in the aorta. Although this receptor works for oxLDL clearance, it was also expressed in macrophages, in which was considered to made lager area of atherosclerosis.

Academic Significance and Societal Importance of the Research Achievements

近年着目されている褐色脂肪であるが、従来から言われているエネルギー代謝経路のみならず、体内の廃棄物である酸化LDLのクリアランスにも大きく関わっていることを受容体レベルから明らかにした。さらに、同受容体は骨格筋にも発現しており、運動負荷などの骨格筋の活性化により酸化LDLの取込量は上昇することが判った。また動脈硬化症モデルマウスを使っての実験を行い、運動と動脈硬化の関係も明らかになってきた。
本研究を進めることにより、古くから言われている「適度な運動が身体に良い」についての科学的な裏付けや運動量の最適化等を行うことができ、健康長寿への指標とすることができると考えている。

Research Products

• [Journal Article] 123I-Labeled oxLDL Is Widely Distributed Throughout the Whole Body in Mice (2017)
  • Author(s): Nakano Atushi、Kawashima Hidekazu、Miyake Yoshinori、Zeniya Tsutomu、Yamamoto Akihide、Koshino Kazuhiro、Temma Takashi、Fukuda Tetsuya、Fujita Yoshiko、Kakino Akemi、Kanaya Shigehiko、Sawamura Tatsuya、Iida Hidehiro
  • Journal Title: Nuclear Medicine and Molecular Imaging Volume: 52 Issue: 2 Pages: 144-153
  • DOI: 10.1007/s13139-017-0497-2
  • Peer Reviewed / Open Access
• [Journal Article] Developmental Endothelial Locus-1 (Del-1) Inhibits Oxidized Low-Density Lipoprotein Activity by Direct Binding, and Its Overexpression Attenuates Atherogenesis in Mice (2016)
  • Author(s): Akemi Kakino, Yoshiko Fujita, Atsushi Nakano, Sayaka Horiuchi, Tatsuya Sawamura
  • Journal Title: Circulation Journal Volume: 80 Issue: 12 Pages: 2541-2549
  • DOI: 10.1253/circj.CJ-16-0808
  • NAID: 130005284982
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lectin-like oxidized low density lipoprotein receptor 1-deficient mice show resistance to instability-induced osteoarthritis (2016)
  • Author(s): K Hashimoto, S Mori, Y Oda, A Nakano, T Sawamura & M Akagi
  • Journal Title: Scand J Rheumatol Volume: 2 Issue: 5 Pages: 1-11
  • DOI: 10.3109/03009742.2015.1135979
  • Peer Reviewed
• [Journal Article] Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin-like oxLDL receptor. (2015)
  • Author(s): Yamamoto K, Kakino A, Takeshita H, Hayashi N, Li L, Nakano A, Hanasaki-Yamamoto H, Fujita Y, Imaizumi Y, Toyama-Yokoyama S, Nakama C, Kawai T, Takeda M, Hongyo K, Oguro R, Maekawa Y, Itoh N, Takami Y, Onishi M, Takeya Y, Sugimoto K, Kamide K, Nakagami H, Ohishi M, Kurtz TW, Sawamura T and Rakugi H.
  • Journal Title: The FASEB Journal Volume: Apr 15 Issue: 8 Pages: 3342-3356
  • DOI: 10.1096/fj.15-271627
  • Peer Reviewed / Open Access
• [Presentation] New findings on oxLDL metabolism using in vivo imaging (2018)
  • Author(s): 中野厚史
  • Organizer: 第23回アディポサイエンス・シンポジウム
• [Presentation] マウス全身イメージングで明らかになってきた、酸化LDLの新たな代謝経路 (2018)
  • Author(s): 中野厚史
  • Organizer: 第14回小動物インビボイメージング研究会
• [Presentation] 健常マウスにおける酸化LDLの体内動態に関する検討：I-123標識体を用いた評価 (2017)
  • Author(s): 河嶋秀和, 中野厚史, 三宅義徳, 銭谷 勉, 越野一博, 山本明秀, 垣野明美, 藤田佳子, 天滿 敬, 沢村達也, 飯田秀博
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2017-03-24
• [Presentation] Imaging and evaluation of brown adipose tissue using 123I-oxLDL (2017)
  • Author(s): 中野厚史
  • Organizer: 第22回アディポサイエンス・シンポジウム
• [Presentation] 123I 標識酸化 LDL による褐色細胞機能評価の可能性 (2016)
  • Author(s): 中野厚史, 河嶋秀和, 天滿 敬, 銭谷 勉, 飯田秀博, 沢村達也
  • Organizer: 第 16 回放射性医薬品・画像診断薬研究会
  • Place of Presentation: 京都市勧業館「みやこめっせ」
  • Year and Date: 2016-10-01
• [Presentation] Whole body imaging of 123I-oxLDL distribution in mouse with high resolution SPECT system (2015)
  • Author(s): Nakano A, Zeniya T, Kawashima H, Iida H, Sawamura T
  • Organizer: JSMI 2015
  • Place of Presentation: 東京
  • Year and Date: 2015-05-21
• [Presentation] 高解像度SPECT を用いたマ ウス酸化LDL全身分布イメージング (2015)
  • Author(s): 中野厚史、銭谷勉、河嶋秀和、飯田秀博、 沢村達也
  • Organizer: 第 10 回日本分子イメージング学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-20