PI3Kgammaは,キナーゼ依存およびキナーゼ依存の異なる効果によって,慢性的な圧力過負荷に対する心臓の反応を調節する
Enrico Patrucco1, Antonella Notte, Laura Barberis
1Department of Genetics, Biology, and Biochemistry, University of Torino, Via Santena 5bis, Italy.
Cell
|August 6, 2004
まとめ
フォスフォノシチド3キナーゼガンマ (PI3Kgamma) は,心臓の機能において二重の役割を担っています. そのキナーゼ活性が心臓の改造に影響を及ぼし,そのキナーゼ独立機能はPDE3Bを介して収縮性を調節する.
科学分野:
- 心血管生物学 心血管生物学
- 分子シグナリング
- 炎症の研究 炎症の研究
背景:
- フォスフォノシチド3キナーゼガンマ (PI3Kgamma) は,Gタンパク質結合受容体活性化酵素である.
- PI3Kgammaは,炎症反応を媒介し,循環性アデノシンモノフォスファート (cAMP) レベルを下げることによって,心臓の収縮性を否定的に調節することが知られている.
研究 の 目的:
- 心臓の生理学と病理学におけるPI3Kガマのキナーゼ活性とキナーゼ独立機能の異なる役割を調査する.
- PI3Kガマが心臓の収縮性と圧力過負荷に対する反応に影響を与えるメカニズムを解明する.
主な方法:
- PI3Kgamma遺伝子の標的型変異によりキナーゼ活性 (PI3KgammaKD/KD) が失われるマウスを使用した.
- PI3KガマKD/KDおよびPI3Kガマ欠乏マウスにおける炎症反応,心臓の収縮性,およびcAMPレベルを評価した.
- 横動脈収縮 (TAC) を用いて誘導された慢性的な圧力過負荷による心筋損傷の評価.
主要な成果:
- PI3KgammaKD/KDのマウスは,炎症反応の減少を示したが,正常な心収縮性とcAMPレベルを維持した.
- PI3Kガンマ欠乏マウスは,PI3KガンマKD/KDマウスとは異なり,TAC.の後に重大な心筋損傷を発症した.
- PI3Kガマは,複合的な調節性フォスフォディエステラゼ3B (PDE3B) 媒介のcAMP分解の重要な成分として特定されました.
結論:
- 心臓PI3Kガマは,キナーゼ依存性およびキナーゼ独立性両方の活性を持っています.
- キナーゼに依存するPI3Kガマ活性がPKB/AktとMAPKのリン酸化に影響し,TAC後の心臓の改造に寄与する.
- キナーゼ独立のPI3Kガマ活性がPDE3Bを調節し,それによって心臓の収縮性を調節する.
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