Role of Ninjurin1, a novel vascular maturation factor, in the regulation of atherosclerotic plaque.

Research Project

Project/Area Number	19K17547
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 53020:Cardiology-related
Research Institution	Asahikawa Medical College
Principal Investigator	Akiho Minoshima 旭川医科大学, 医学部, 助教 (90645962)
Project Period (FY)	2019-04-01 – 2022-03-31
Project Status	Completed (Fiscal Year 2021)
Budget Amount *help	¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000) 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords	虚血性心疾患 / vasa vasorum / 不安定プラーク / 血管成熟化 / Ninjurin1
Outline of Research at the Start	これまで血管成熟化を制御する新規分子Ninjurin1(Ninj1)を見出し、新生血管の幼若化をもたらす血管特異的Ninj1欠損誘導マウスを作製した。このユニークな動物モデルを用いて血管外膜の栄養微小血管(vasa vasorum)の成熟化障害や形成異常とプラークの進展や不安定化との因果関係を実証する。 Ninj1とアポE両欠損マウスを用いた動脈硬化症モデルを作製し、プラーク内の微小血管形成異常がプラーク増悪・不安定化をもたらすか確認する。あわせて、臨床での冠動脈インターベンション症例で採取したプラーク組織の三次元解析でプラーク内微小血管形成やNinj1発現と臨床病態との関連性を検証する。
Outline of Final Research Achievements	This study aims to demonstrate that Ninjurin1 (Ninj1), a novel molecule that regulates vascular maturation, contributes to plaque stabilization through the maturation and stabilization of microvessels (vasa vasorum, VV) that nourish the vessel wall and extend from the outer vascular membrane to the plaque. In experiments using mice, we confirmed that pericyte-specific knocked out of Ninj1 causes juvenile and fragile VV formation and worsens the pathogenesis of vascular remodeling. Evaluation using clinical coronary plaque tissue showed that microvessels within the plaque tended to be smaller and denser in patients with high LDL cholesterol levels, suggesting that this vascular infantilization may influence plaque destabilization.
Academic Significance and Societal Importance of the Research Achievements	心血管や脳虚血疾患の基盤病態である動脈硬化症の発症進展に関して、従来の『血管内膜の障害』に加え、『血管外膜の栄養微小血管(vasa vasorum,VV)の形成異常』がプラーク増悪や不安定化に関連することが推測されている。これは臨床的な状況知見から推測されてきたものであるが、両者の因果関係を明確に示すエビデンスは少なく、結果として、その先にある「血管外膜部を標的とする動脈硬化治療の開発」に至っていない。 Ninj1を介した血管外膜の微小血管VVの成熟化が、プラーク形成や不安定化に関与することを証明することにより、Ninj1を治療、検査のターゲットとした新たな治療戦略につながる可能性がある。

Report

(4 results)

2021 Annual Research Report Final Research Report ( PDF )
2020 Research-status Report
2019 Research-status Report

Research Products

(2 results)

All Journal Article (1 results) (of which Int'l Joint Research: 1 results, Peer Reviewed: 1 results, Open Access: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

[Journal Article] Pericyte-specific deletion of Ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature2021
- Author(s)
  Kiwamu Horiuchi, Kohei Kano, Akiho Minoshima, Taiki Hayasaka, Atsushi Yamauchi, Takamitsu Tatsukawa, Risa Matsuo, Yuri Yoshida, Yui Tomita, Maki Kabara, Naoki Nakagawa, Naofumi Takehara, Naoyuki Hasebe, and Jun-ichi Kawabe
- Journal Title
  
  American Journal of Physiology Heart and Circulatory Physiology
  
  Volume: - Issue: 6 Pages: H2438-H2447
- DOI
  10.1152/ajpheart.00931.2020
- Related Report
  2020 Research-status Report
- Peer Reviewed / Open Access / Int'l Joint Research
[Presentation] Pericyte-specific deletion of Ninjurin1 induces abnormal vasa vasorum formation and enhances intimal hyperplasia2019
- Author(s)
  Kiwamu Horiuchi , Akiho Minoshima , Maki Kabara , Kohei Kano , Yui Tomita , Yuri Yoshida , Taiki Hayasaka , Naofumi Takehara , Naoyuki Hasebe , Jun-ichi Kawabe
- Organizer
  European Society of Cardiology
- Related Report
  2019 Research-status Report
- Int'l Joint Research