Identification of an endogenous oxidized LDL blocker and elucidation of its regulatory mechanism of arteriosclerotic diseases

• Project/Area Number: 25670133
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Shinshu University (2014-2015); National Cardiovascular Center Research Institute (2013)
• Principal Investigator: KAKINO Akemi 信州大学, 先鋭領域融合研究群バイオメディカル研究所, 助教(特定雇用) (00534637)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 酸化LDL / 酸化LDL受容体 / 動脈硬化

Outline of Final Research Achievements

Oxidized LDL (oxLDL) is implicated in atherosclerosis. Despite their potential importance, however, endogenous inhibitors that block the interaction between oxLDL and its receptors have not been extensively studied. To address this issue, we investigated whether developmental endothelial locus-1 (Del-1) might function as an endogenous inhibitor of oxLDL. Del-1 selectively bound to oxLDL. Del-1 inhibited oxLDL uptake and oxLDL-induced cellular responses irrespective of the kind of scavenger receptor. Moreover, Del-1 overexpression attenuated atherogenesis in mice. These results suggested that disrupted balance among modified LDL, scavenger receptors, and protective molecules might lead to the progression of atherosclerosis.

Research Products

• [Journal Article] Modified LDL functions in human and LOX-1-mediated signal transductions (2016)
  • Author(s): Kakino, A., Sawamura, T.
  • Journal Title: Folia Pharmacologica Japonica Volume: 147 Issue: 2 Pages: 107-113
  • DOI: 10.1254/fpj.147.107
  • NAID: 130005125650
  • ISSN: 0015-5691, 1347-8397
• [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
• [Journal Article] 変性LDLとsLOX-1のバイオマーカーとしての意義 (2015)
  • Author(s): 垣野明美, 沢村達也
  • Journal Title: 動脈硬化予防 Volume: 14 Pages: 40-45
• [Journal Article] Lectin-like oxidized low-density lipoprotein recepto-r1 abrogation causes resistance to inflammatory bone destruction in mice, despite promoting osteoclastogenesis in the steady state. (2015)
  • Author(s): Nakayachi M, Ito J, Hayashida C, Ohyama Y, Kakino A, Okayasu M, Sato T, Ogasawara T, Kaneda T, Suda N, Sawamura T, Hakeda Y.
  • Journal Title: Bone Volume: 75 Pages: 170-182
  • Peer Reviewed
• [Presentation] Identification of oxLDL blocking protein and its anti-atherogenic function (2016)
  • Author(s): Kakino, A., Nakano, A., Fujita, Y., Sawamura, T.
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2016-03-22
• [Presentation] AT1はLOX-1を介した酸化LDLによるシグナル伝達を促進する (2015)
  • Author(s): 垣野明美、山本浩一、藤田佳子、楽木宏美、沢村達也
  • Organizer: 第1回J-ISCP学術集会
  • Place of Presentation: ハイアットリージェンシー京都（京都）
  • Year and Date: 2015-06-20
• [Presentation] PAF receptor interacts with LOX-1 and promotes oxidized LDL-induced cellular responses (2015)
  • Author(s): Kakino, A., Fujita, Y., Yamamoto, K., Rakugi, H., Sawamura, T.
  • Organizer: 17th International Congress on Atherosclerosis
  • Place of Presentation: Amsterdam RAI Congress Centre (オランダ)
  • Year and Date: 2015-05-23
  • Int'l Joint Research
• [Presentation] AT1 promotes oxLDL-induced cell responses through interact with LOX-1. (2015)
  • Author(s): Kakino A, Yamamoto K, Li L, Fujita Y, Rakugi H, Sawamura T
  • Organizer: 第92回日本生理学会大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Interaction between AT1 and LOX-1 promote oxLDL-induced cell responses. (2015)
  • Author(s): Kakino A, Yamamoto K, Li L, Fujita Y, Rakugi H, Sawamura T
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Overexpression of Del-1, an oxLDL blocking protein, suppressed atherogenesis in mice without lowering oxLDL concentration, but with reducing LOX-1 ligand containing apoB activity (LAB) (2014)
  • Author(s): Kakino A, Nakano A, Fujita Y, Sawamura T
  • Organizer: 2014 AACC ANNUAL MEETING
  • Place of Presentation: USA, Chicago
  • Year and Date: 2014-07-29 – 2014-07-30
• [Presentation] AT1 directly interacting with LOX-1 mediates signal transduction induced by oxidized LDL. (2014)
  • Author(s): Kakino A, Yamamoto K, Li L, Fujita Y, Rakugi H, Sawamura T
  • Organizer: The 82nd Congress of the European Atherosclerosis Society (EAS 2014)
  • Place of Presentation: Spain, Madrid
  • Year and Date: 2014-05-31 – 2014-06-03
• [Presentation] 酸化LDL作用の新しい抑制機構 (2013)
  • Author(s): 垣野明美
  • Organizer: 第14回Pharmaco-Hematologyシンポジウム
  • Place of Presentation: 東京
• [Presentation] An endogenous blocker of oxidized LDL (2013)
  • Author(s): Akemi Kakino, Atsushi Nakano, Yoshiko Fujita, Tatsuya Sawamura
  • Organizer: 13th International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] 内因性蛋白質による新しい酸化LDL作用阻害機構 (2013)
  • Author(s): 垣野明美、中野厚史、藤田佳子、沢村達也
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] Identification of Endogenous Anti-Atherogenic Protein Which Blocks the Interaction between Oxidized LDL and Its Receptors (2013)
  • Author(s): Akemi Kakino, Atsushi Nakano, Yoshiko Fujita, Tatsuya Sawamura
  • Organizer: AHA Scientific Sessions 2013
  • Place of Presentation: Dallas, Texas
• [Presentation] Del-1は酸化LDL－受容体相互作用を阻害し、血管壁脂質沈着を抑制する (2013)
  • Author(s): 垣野明美、中野厚史、藤田佳子、沢村達也
  • Organizer: 第17回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 大阪
• [Presentation] 酸化LDL阻害分子Del-1の過剰発現は、マウス血管壁脂質沈着を抑制する (2013)
  • Author(s): 垣野明美、中野厚史、藤田佳子、沢村達也
  • Organizer: 第23回日本循環薬理学会
  • Place of Presentation: 福岡