6-メルカプトプーリンによって核受容体Nur77の活性化により,ネオインティマ形成から保護されます
Nuno M M Pires1, Thijs W H Pols, Margreet R de Vries
1Gaubius Laboratory, TNO-Quality of Life, Leiden, The Netherlands.
Circulation
|January 24, 2007
まとめ
6-メルカプトプーリン (6-MP) は,核受容体Nur77.7を活性化することによって,血管の滑らかな筋肉細胞の増殖と復元を阻害する. この活性化は,DNA合成とネオインティマの形成を減少させ,インステント回復症に対する潜在的な治療法を提供します.
科学分野:
- 心血管生物学 心血管生物学
- 分子医学は分子医学である.
- 薬理学 薬理学とは
背景:
- 経皮冠動脈手術の合併症であるレステノシスは,血管性滑らかな筋肉細胞 (SMC) の過剰な増殖を伴う.
- 核受容体Nur77は,SMCに富んだ病変形成に対する保護因子として特定されています.
- 6-メルカプトプーリン (6-MP) は,Nur77の活性を増強することが知られている.
研究 の 目的:
- 6-MPがNur77.7の活性化によりネオインティマ形成を抑制するという仮説を検証する.
- Nur77の活動に関連して,6-MPがSMCの増殖とネオインティマ形成に影響する分子メカニズムを解明する.
主な方法:
- Nur77のノックダウンのための小さな干渉RNAを使用して,培養SMCのNur77活動とDNA合成に6-MPの影響を評価しました.
- 6MPのインビボ効果を研究するために,マウスモデルでのマフ誘発性ネオインティマ形成を用いた.
- 野生型およびNur77-トランスジェニックマウスの薬剤排出カフスを介して局所的に6-MPを投与した.
主要な成果:
- 6-MPは,培養されたSMCでNur77の活性を増やし,DNA合成を減少させ,Nur77のノックダウンによって部分的に逆転した.
- In vivoでは,局所的な6-MP投与は,増殖する細胞核抗原を減少させ,p27 (Kip1) レベルを増加させることで,野生型のマウスのネオインティマ形成を著しく抑制しました.
- ネオインティマ形成の抑制が強化されることは,Nur77を過剰に発現したマウスで観察されたが,6MPは,Nur77のドミナントネガティブなマウスでは効果がなかった.
結論:
- 6-MPは,Nur77の活性を増強することによって,SMCの増殖とネオインティマの形成から保護します.
- 核受容体Nur77の活性化は,インステント回復症の治療のための有望な治療戦略です.
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