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血管の滑らかな筋肉細胞における酸化性DNA損傷の欠陥ベース切除修復は,動脈硬化を促進する
Aarti Shah1, Kelly Gray1, Nichola Figg1
1Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, United Kingdom. Dr Gray is currently at Cardiovascular Safety, AstraZeneca, Cambridge, United Kingdom.
Circulation
|April 13, 2018
まとめ
動脈硬化性プラークの血管滑らかな筋肉細胞 (VSMC) は,OGG1酵素の活性が低下したため,8- オクソグアニンの (8oxoG) 修復が妨げられています. この修復メカニズムの復元は 動脈硬化症の進行を大幅に減少させます
科学分野:
- 心血管生物学
- DNA 修復 メカニズム
- 酸化ストレスに関する研究
背景:
- 動脈硬化性プラークは,主に8-オキシグアニン (8oxoG) 病変による重要な酸化DNA損傷を蓄積する.
- 血管滑らかな筋肉細胞 (VSMC) の 8oxoG レベルと修復を制御するメカニズムと,動脈硬化におけるその役割は不明である.
研究 の 目的:
- 人間の動脈硬化性VSMCにおける8oxoGの蓄積と修復酵素の調節を調査する.
- VSMC機能と動脈硬化における8-オキシグアニンDNAグリコシラーゼI (OGG1) とそのアセチル化の役割を明らかにする.
- 動脈硬化症のモデルにおける酸化性DNA損傷の軽減の治療の可能性を評価する.
主な方法:
- 人間の動脈硬化プラークとVSMCにおける8oxoG濃度とOGG1活性に関する分析.
- VSMCにおけるp300とシルトゥイン1によるOGG1アセチル化のインビトロ研究
- 動脈硬化症の進行を評価するために,VSMC特異的なOGG1発現または欠陥を持つApoE-/-マウスモデルを生成し,研究する.
主要な成果:
- 人間の動脈硬化性VSMCは,p300とシルトゥイン1によって調節される,OGG1アセチレーションの減少に関連した8oxoG修復を呈する.
- VSMCにおけるp300値の低下は,酸化ストレス下でのOGG1アセチル化に寄与する.
- VSMC特異のOGG1発現は,アセチル化欠陥の変異体ではなく,ApoE/- マウスの8oxoG,DNA損傷,動脈硬化症を有意に減少させた.
結論:
- OGG1機能不全によって媒介されるVSMCにおける8oxoG塩基切除修復は,動脈硬化症の重要な要因である.
- p300/シルチューイン1媒介のOGG1アセチル化は,VSMCの機能を維持し,酸化的損傷を防ぐために重要である.
- OGG1の活性を増やすことで8oxoGの蓄積を狙うことは,動脈硬化症の進行を抑えるための有望な治療戦略です.
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