Ca2+/カルモジュリン依存タンパク質キナーゼIIとタンパク質キナーゼAは,ヒトの心臓病理学におけるサルコプラズマ網膜のCa2+漏れを差異的に調節する
Thomas H Fischer1, Jonas Herting, Theodor Tirilomis
1Abteilung Kardiologie und Pneumologie/Herzzentrum, Georg August Universität Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
Circulation
|July 24, 2013
まとめ
心不全では,サルコプラズマ網膜のCa2+の漏れが増加することが,ライオノジン受容体2型 (RyR2) 機能障害と関連している. Ca(2+) /カルモジュリン依存タンパク質キナーゼII (CaMKII) 抑制は,不律症と収縮機能障害の治療に有望であることが示されています.
科学分野:
- 心血管生物学 心血管生物学
- 分子心臓病学 分子心臓病学
- バイオケミストリー バイオケミストリー
背景:
- リアノジン受容体2型 (RyR2) 機能不全によるサルコプラズマ網膜 (SR) Ca(2+) の漏れは,ヒトの心不全 (HF) に際して極めて重要です.
- 心筋縮からHFへの漸進的なRyR2不調のメカニズムは依然として議論の余地があります.
研究 の 目的:
- カルモジュリン依存タンパク質キナーゼII (CaMKII) /カルモジュリン依存タンパク質キナーゼII (CaMKII) とタンパク質キナーゼA (PKA) がRyR2リン酸化とSRCa2+) リークにおいて,心筋縮からHFへの移行時に果たす役割を調査する.
- HFにおけるCaMKIIおよびPKA阻害の治療の可能性を評価する.
主な方法:
- 健康な対照群,補償性高縮症の患者,およびHFの患者からの心筋組織の分析.
- RyR2のリン酸化レベルとSR Ca2+) 漏れを測定する.
- CaMKIIおよびPKA阻害剤のSR Ca2+) ハンドリングに対する影響の評価.
主要な成果:
- ハイパートロフィーでは,CaMKIIとPKAの両方がRyR2をリン酸化し,それらの阻害剤はSR Ca2+) の漏れを減少させた.
- HFでは,SR Ca(2+) の漏れがほぼ2倍になり,CaMKII依存型RyR2のリン酸化が増加した.
- CaMKIIの阻害は,HFにおけるSRCa2+) リークを減少させ,PKAの阻害はSRCa2+) 負荷とシストリック機能を悪化させた.
結論:
- ハイパルトロフィーでは,CaMKIIとPKAがRyR2とSRCa2+) の漏れを調節する.
- HFへの移行は,Ca2+流出が増加し,Ca2+循環が乱され,CaMKII依存型RyR2酸化が増加している.
- CaMKII阻害は,HFに関連する心律不整症と収縮機能障害に対する潜在的な治療戦略を表しています.
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