ロキナーゼは,低酸素誘発による内皮酸化窒素合成酵素のダウンレギュレーションを媒介する
Masao Takemoto1, Jianxin Sun, Junko Hiroki
1Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Mass 02139, USA.
Circulation
|July 3, 2002
まとめ
低酸素症は,Rho-キナーゼシグナル伝達を通じて,内皮中の窒素酸化物合成酵素 (eNOS) の発現を低下させる. ロキナーゼ阻害剤は,この効果を逆転させ,低酸素誘発性肺高血圧の潜在的な治療法を提供します.
科学分野:
- 心血管科学の研究について
- 分子生物学は分子生物学である.
- 細胞生理学 細胞生理学
背景:
- 低酸素誘発性肺高血圧は,病気と死亡の重要な原因です.
- 低酸素症は,内皮酸化窒素合成酵素 (eNOS) の発現を低下させ,肺血管収縮を引き起こす.
- eNOS発現の低酸素減少の背後にある正確なメカニズムは不明ですが,Rho-kinaseを含む可能性があります.
研究 の 目的:
- 低酸素が,ロキナーゼシグナル伝達を通してeNOSの発現を調節するかどうかを調査する.
- eNOS発現と活性における低酸素誘発による変化におけるロキナーゼの役割を決定する.
主な方法:
- 人間のサフェヌス動脈と肺動脈の内皮細胞は,低酸素 (3%O2) に晒された.
- 細胞はRho-キナーゼ阻害剤 (ヒドロキシファスジル) または他のRho/Rho-キナーゼ調節剤で治療された.
- eNOS mRNA,タンパク質発現,活性,mRNA半減期を測定した.
主要な成果:
- 低酸素は,ロキナーゼの発現と活性を増加させた.
- 低酸素症は,eNOSのmRNAとタンパク質発現を低下させ,eNOSの活性を抑制した.
- Rho-キナーゼ阻害,Rho阻害,またはアクチン細胞骨格の破壊は,低酸素誘発 eNOSのダウンレギュレーションを逆転させた.
- 低酸素症は,eNOS mRNAの半減期を短縮し,この効果はヒドロキシファスジルによって逆転した.
結論:
- eNOS発現の低酸素誘発の減少は,Rho-キナーゼによって媒介されます.
- ロキナーゼ阻害剤は,低酸素誘発性肺高血圧に対する潜在的な治療価値を示しています.
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