核eNOSはADAR1とS-ニトロ酸と相互作用し,I型インターフェロン信号と内皮機能を調節する
Xiaozhu Zhou1, Carsten Kuenne2, Stefan Günther2
1Institute for Vascular Signaling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany (X.Z., B.G., F.D.L., I.F., M.S.).
Circulation
|October 29, 2025
まとめ
核内皮酸化窒素合成酵素 (eNOS) は,ADAR1経由でRNA編集を調節し,血管の恒常性を維持する. eNOSの機能の喪失はこれを阻害し,タイプIインターフェロンのシグナル伝達を活性化し,動脈硬化に寄与する.
科学分野:
- 血管生物学
- 分子生物学
- 免疫学
背景:
- 内皮 NO 合成酵素 (eNOS) によって生成される内皮酸化窒素 (NO) は,血管の恒常性および抗炎症反応に不可欠です.
- ENOSは通常は膜に結合していますが,内皮細胞核にも存在し,その核の役割に関する調査を促しています.
研究 の 目的:
- 内皮細胞における核 eNOSとその関連 NO 信号の機能的重要性を調査する.
- 核 eNOS を内皮細胞機能と血管健康に結びつける分子メカニズムを解明する.
主な方法:
- コンフォカル顕微鏡,生化学分析,組織学,マルチオミクスと組み合わせた eNOS機能喪失モデルを使用した.
- 動脈硬化症のマウスモデルとヒト患者のサンプルでの病理学的関連性を評価した.
主要な成果:
- 核 eNOSはヒトとマウンの内皮細胞で特定され,VEGF刺激により核の存在が強化された.
- 核eNOSはRNA編集に不可欠なADAR1を含むRNA結合タンパク質と相互作用する.
- eNOS欠乏はADAR1編集の障害,二重鎖RNAの増加,MAVSの集積,I型インターフェロンシグナリングの活性化,および細胞サイクル遺伝子発現の変化をもたらし,最終的に増殖を減少させ,細胞死亡を増加させた.
- 動脈硬化における内皮機能障害は,二重鎖RNAとI型インターフェロンシグナル伝達の増加と相関する.
結論:
- 血管の恒常性を維持するためにADAR1の活性を核 eNOSから派生したNOが調節する新しい経路を発見.
- NOの生物学的利用性が低下すると,以前は認識されていないI型インターフェロン反応が内皮で発生し,アテロゲネシスを促進する.
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