成長因子β-活性化キナーゼ1信号伝達経路の変換は,心筋の生存と再構成を決定的に調節する

Lei Li¹, Yi Chen¹, Jessica Doan¹

¹From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (L.L., Y.C., J.D., J.M., Q.L.); and Howard Hughes Medical Institute, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.).

Circulation

|October 4, 2014

まとめ

成長因子β活性化キナーゼ1 (TAK1) を変換することは,心臓の健康に不可欠です. その欠如はプログラムされた死滅 (necroptosis) を誘発し,心不全とマウスの有害な改造につながります.

科学分野:

心血管生物学心血管生物学
細胞死メカニズム細胞死メカニズム
分子シグナリング

背景:

プログラムされた死滅 (necroptosis) は,発達と疾患において極めて重要であるが,その心臓の調節は不明である.
筋臓の改造と心不全におけるネクロプトーシスの役割については,さらなる調査が必要である.

研究の目的:

成長因子β活性化キナーゼ1 (TAK1) の変換が心臓死滅を調節する役割を調査する.
TAK1が心筋の再編成と心不全に影響を与える分子メカニズムを解明する.

主な方法:

マウスのマップ3k7 (TAK1をコードする) の心臓特異的遺伝子アブレーション.
ミオサイトアポトーシスとネクロプトーシスの分析.
心筋再建と心不全マーカーの評価.
腫瘍死滅因子受容体-1 (TNFR1) 信号伝達経路の調査.

主要な成果:

心臓特異的なMap3k7アブレーションにより,自発的なアポトーシスとネクロプトーシスが誘発され,有害なリモデリングと心不全を引き起こしました.
これらの効果はTNFR1の信号伝達に依存していた.
TAK1はTNFR1シグナル伝達における分子スイッチとして作用し,RIP1,FADD,カスパース8を含む細胞死複合体の形成を調節する.
RIP1またはRIP3の阻害は,TAK1欠乏したマウスの死滅性細胞死亡と心不全を改善しました.

結論:

TAK1は心臓における重要な生存因子であり,死滅を直接抑制する.
TAK1は,心筋ホメオスタシスを維持し,有害な改造を防ぐために不可欠です.
TAK1媒介性ネクロプトーシス経路をターゲットにすることで,心不全の治療戦略を提供することができる.

キーワード:

アポプトシス (apoptosis) とは心不全とは,心不全である.筋細胞,心臓,心臓ネクロシス・ネクロシスシグナルトランスデュークション信号.静脈のリモジリング

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