シーア誘発CCN1はアテロプロン内皮現象と動脈硬化を促進する
Pei-Ling Hsu1,2, Jheng-Sin Chen1, Chin-Yung Wang1
1Department of Cell Biology and Anatomy (P.-L.H., J.-S.C., C.-Y.W., F.-E M.), College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Circulation
|March 29, 2019
まとめ
マトリセルタンパク質CCN1は,内皮細胞における核因子-κBを活性化することによって,動脈硬化を促進する. T1ペプチドとのCCN1-インテグリンα6β1結合を阻害することは,このプロセスを阻害し,動脈硬化症の潜在的な治療戦略を提供します.
科学分野:
- 心血管生物学
- 分子医学
- 細胞生物学
背景:
- 動脈硬化症の発症は血管の血流の障害と関連しています.
- マトリセルタンパク質CCN1は,内皮細胞の流れが乱され,動脈硬化病変で上位調節される.
- 動脈硬化病原性におけるCCN1の特定の役割は不明でした.
研究 の 目的:
- 動脈硬化症におけるCCN1の in vivoおよびin vitro機能を調査する.
- CCN1がフロー条件下で内皮細胞の行動に影響を与える分子メカニズムを解明する.
主な方法:
- 動脈硬化におけるCCN1の役割を研究するためにノックインマウス (Ccn1-dm/Apoe-/-) を生成した.
- 内皮細胞 (ヒトとマウス) の上での切断ストレス実験を,ラミナールと振動的な流れで利用した.
- 評価されたプラーク形成,酸化ストレス,炎症マーカー,核因子-κB (NF-κB) の活性化.
主要な成果:
- 動脈硬化病変の進行に伴い,Ccn1の発現が増加した.
- Ccn1-dm/Apoe-/マウスは,対照群と比較して,動脈硬化症の発症に対する有意な抵抗を示した.
- 酸化ストレス,炎症マーカー,単細胞ホーミングがCcn1-dm/Apoe-/マウスで減少した.
- CCN1/α6β1シグナリングによるフロー誘発のNF-κB活性化,アテロプロン遺伝子発現を促進する.
- CCN1/α6β1とNF-κBの間のポジティブなフィードバックループが特定され,それはCcn1-dm変異またはT1ペプチドによって破壊された.
結論:
- CCN1は,内皮細胞のフェノタイプを調節することによって,動脈硬化に起因的な役割を果たします.
- CCN1はインテグリンα6β1を結合してNF-κBを活性化させ,アテロゲネシスを誘発する自己永続的なサイクルを生み出します.
- CCN1-α6β1の相互作用を標的とするT1ペプチドは,新しい動脈硬化治療薬の開発の可能性を示しています.
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