The Role of Blood Fibrinolytic Factor Plasmin Activity in Manipulating Macrophage-mediated Mechanisms of Atherosclerosis Promotion

• Project/Area Number: 18K16081
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nagoya City University (2019-2021); Hamamatsu University School of Medicine (2018)
• Principal Investigator: Miyajima Chiharu 名古屋市立大学, 医薬学総合研究院(薬学), 講師 (40770798)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: マクロファージ / 動脈硬化 / プラスミノーゲン / Plasminogen

Outline of Final Research Achievements

In this study, we analyzed the effect of plasminogen (Plg) on the development of atherosclerosis in mice double-deficient (Ldlr-/-/Apobec1-/-) in the LDL receptor and RNA-editing enzyme APOBEC1, a mouse model of human type IIa familial hyperlipidemia, the most common form of hyperlipidemia in humans. Plg did not affect the expression of scavenger receptors involved in LDL uptake by Mφ, suggesting a novel pathogenetic mechanism that controls Mφ atherosclerosis progression by directly regulating LDL size.

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義はヒトのLDL-C高脂血症を反映するLdlr-/-/Apobec1-/-マウスを用いて、動脈硬化に対するPlg/Plm活性化システムの影響を解明している点にある。多くの研究に汎用されているApoe-/-マウスはIII型のモデルであり、大多数のヒト家族性高脂血症の病態を反映していない。申請者らはLdlr-/-/Apobec1-/-マウスを用いて、動脈硬化の発症・促進に、Mφ上におけるPlg/Plmを介した血液線溶系の活性化が重要であると見出した。本研究により、動脈硬化へのPlg/Plmの機能が解明され、Plg/Plm活性化システムに標的を絞った特異的な薬の開発にも繋がる。

Research Products

• [Journal Article] Anti-Inflammatory Activity of Kurarinone Involves Induction of HO-1 via the KEAP1/Nrf2 Pathway (2020)
  • Author(s): Sakiko Nishikawa, Yasumichi Inoue, Yuka Hori, Chiharu Miyajima, Daisuke Morishita, Nobumichi Ohoka, Shigeaki Hida, Toshiaki Makino, Hidetoshi Hayashi
  • Journal Title: Antioxdants Volume: 9 Issue: 9 Pages: 842-842
  • DOI: 10.3390/antiox9090842
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence (2020)
  • Author(s): Miyajima Chiharu、Kawarada Yuki、Inoue Yasumichi、Suzuki Chiaki、Mitamura Kana、Morishita Daisuke、Ohoka Nobumichi、Imamura Takeshi、Hayashi Hidetoshi
  • Journal Title: Cells Volume: 9 Issue: 1 Pages: 171-171
  • DOI: 10.3390/cells9010171
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia. (2018)
  • Author(s): Miyajima C, Iwaki T, Umemura K, Ploplis VA, Castellino FJ
  • Journal Title: Biomed Res Int Volume: - Pages: 1878964-1878964
  • DOI: 10.1155/2018/1878964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 転写共役因子 TAZ によるがん抑制遺伝子 p53 の活性抑制を介した細胞老化制御機構の解明 (2021)
  • Author(s): 宮嶋ちはる
  • Organizer: 第44回日本分子生物学会
• [Presentation] Transcriptional Coactivator TAZ Negatively Regulates Tumor-Suppressor p53 Activity (2020)
  • Author(s): 宮嶋ちはる
  • Organizer: 第43回分子生物学会
• [Presentation] 脱ユビキチン化酵素USP17による 脂質代謝関連転写因子SREBPタンパク制御機構の解析 (2020)
  • Author(s): 柏原翔陽
  • Organizer: 第19回次世代を担う若手のためのファーマ・バイオフォーラム2020
• [Presentation] 脱ユビキチン化酵素USP28はEMT関連転写因子Snailを安定化してがん細胞の浸潤を促進する (2020)
  • Author(s): 中本 遥菜
  • Organizer: フォーラム2020 衛生薬学・環境トキシコロジー
• [Presentation] 脱ユビキチン化酵素USP28はEMT関連転写因子Snailを安定化してがん細胞の浸潤を促進する (2020)
  • Author(s): 中本 遥菜
  • Organizer: 日本薬学会 東海支部2020
• [Presentation] 高LDL血症におけるマクロファージ泡沫化に対するPlasmin活性の役割 (2019)
  • Author(s): 宮嶋ちはる
  • Organizer: 第20回 pharmaco-hematologyシンポジウム
• [Presentation] Foam Cell Formation is Regulated by Plasmin in a Murine Model of Type Ⅱa Familial Hypercholesterolemia (2019)
  • Author(s): 宮嶋ちはる
  • Organizer: 第92回日本薬理学会
• [Presentation] The Activation of Plasmin/Plasminogen system Accelerates Atherosclerosis in a Murine Model of Type Ⅱa Familial Hypercholesterolemia (2018)
  • Author(s): Chiharu Miyajma
  • Organizer: 第18回慶北-浜松合同医学シンポジウム浜松会議
• [Presentation] Plasmin Activity Promotes Atherosclerosis in a Murine Model of Type IIa Familial HypercholesterolemiaPlasminogen Deficiency Attenuates Atherosclerosis in a Murine Model of Type Ⅱa Familial Hypercholesterolemi (2018)
  • Author(s): Chiharu Miyajma
  • Organizer: 第40回血栓止血学会
• [Presentation] Plasminogen Deficiency Attenuates Atherosclerosis in a Murine Model of Type IIa Familial Hypercholesterolemia (2018)
  • Author(s): Chiharu Miyajma
  • Organizer: XXVI ISTH Congress and 63rd Annual Scientific and Standardization Committee (SSC) Meeting
  • Int'l Joint Research