サイクロオキシゲネーゼ2系プロスタサイクリンは,シルトゥイン1に依存した方法で組織因子を抑制することにより,動脈血栓形成を調節する
Silvia S Barbieri1, Patrizia Amadio, Sara Gianellini
1Centro Cardiologico Monzino, IRCCS, Via Parea 4, 20138 Milano, Italy. silviabarbieri@yahoo.com
Circulation
|August 7, 2012
まとめ
選択性サイクロオキシゲナーゼ-2 (COX-2) 阻害剤は,血栓形成のリスクを増加させます. COX-2の消去は,プロスタサイクリンとシルトゥイン-1 (SIRT1) を減少させ,組織因子 (TF) を増加させることで,血栓形成を高めます.
科学分野:
- 心血管生物学 心血管生物学
- トロンボシス研究研究
- 薬理学 薬理学とは
背景:
- 選択性サイクロオキシゲナーゼ-2 (COX-2) 阻害剤は,心筋梗塞と血栓性イベントの増加と関連しています.
- これらの血栓性リスクの背後にある正確なメカニズムは,まだ完全に理解されていません.
研究 の 目的:
- COX-2が動脈血栓形成に影響を与えるメカニズムを解明する.
- COX-2媒介の血栓形成におけるプロスタサイクリン,ペロキシゾーム増殖因子活性化受容体-δ (PPARδ),およびシルトゥイン-1 (SIRT1) の役割を調査する.
主な方法:
- COX-2ノックアウトと野生型のマウスの鉄塩化物誘発性動脈血栓形成の比較.
- 血小板の貢献度を評価するためのクロス輸血実験.
- プロスタサイクリン合成酵素,ペロキシソーム増殖器活性化受容体-δ,シルトゥイン-1 (SIRT1),および組織因子 (TF) の発現と活性に関する分析.
- プロスタサイクリンとPPARδ経路の薬理学的な調節,およびSIRT1の抑制/活性化.
主要な成果:
- COX-2ノックアウトマウスは,野生型のマウスと比較して,著しく大きな動脈血栓形成を示した.
- COX-2のデリレーションにより,プロスタサイクリンとSIRT1の発現が低下し,その結果,組織因子 (TF) の凝固の開始が増加しました.
- プロスタサイクリンまたはPPARδアゴニズムはCOX-2ノックアウトマウスのプロトロンボティック現象型を逆転させ,野生型のマウスのアンタゴニズムは血栓形成を促進した.
- SIRT1の阻害はTF活性と血栓形成を増加させ,SIRT1の活性化はCOX-2ノックアウトマウスのTF活性と前血栓状態を減少させた.
結論:
- プロスタサイクリン/PPARδ経路は,SIRT1とTFを調節し,動脈血栓形成を制御する新しいメカニズムを表します.
- これらの経路を介してSIRT1とTFを標的にすることは,COX-2阻害剤に関連したアテロトロンボティック合併症の治療戦略を提供することができます.
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