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心不全の治療法としてNAD+レドックスバランスの正常化

Chi Fung Lee¹, Juan D Chavez¹, Lorena Garcia-Menendez¹

¹From Mitochondria and Metabolism Center (C.F.L., L.G.-M., Y.C., N.D.R., R.T.), Department of Anesthesiology and Pain Medicine (C.F.L., L.G.-M, Y.C., N.D.R., R.T.), Department of Genome Sciences (J.D.C., J.E.B.), Department of Pathology (Y.A.C.), and Department of Medicinal Chemistry (J.S.E., Y.A.G., D.R.G.), University of Washington, Seattle, WA.

|August 5, 2016

まとめ

心不全におけるミトコンドリア機能障害は,タンパク質の過酸化とNAD (−) リドックス不均衡と関連しています. NAD ((+) のレベルを回復させることで心臓の機能が改善され,心臓不全の治療策として有望な結果が得られます.

科学分野:

心臓病科
ミトコンドリア生物学
生物化学

背景:

ミトコンドリア機能障害は心不全の発症の重要な要因です
現在,ミトコンドリア機能障害を直接に対処する治療法は存在しない.
タンパク質アセチル化とニコチナミドアデニンジヌクレオチド (NADH/NAD+) の比率はミトコンドリア機能の重要な調節因子である.

研究の目的:

心不全におけるタンパク質アセチル化とNADH/NAD+比の役割を調査する.
特定のタンパク質アセチル化部位の機能的影響を決定する.
ミトコンドリアのタンパク質アセチル化を正常化する治療の可能性を評価する.

主な方法:

失敗したヒトとマウスの心臓でNADH/NAD+比とタンパク質アセチル化を評価した.
プロテオームとアセチロームを分析した.
分子ドッキング,ミュータゲネシス,カルシウム吸収アッセイを用いた.
NAD+プールを拡張することで治療的介入をテストした.

主要な成果:

人間とマウスの心臓の衰えは,NADH/NAD+の比率とタンパク質の過酸化を示しています.
NAD+レベルを上昇させることで,過酸化,心筋縮が減り,心筋機能が改善された.
シャトルタンパク質のハイパーアセチル化により,NADHの輸送が妨げられ,エネルギー不足を引き起こした.
ATP合成複合体のコンポーネントのアセチル化により,ミトコンドリアの透性移行の毛穴開きが促進された.

結論:

NAD+ リドックス不均衡によって引き起こされるミトコンドリアタンパク質の過酸化は,2つのメカニズムを通じて心不全に寄与する.
NADH/NAD+不均衡の正常化は,心不全の臨床前モデルにおいて有意な治療効果を示している.
NAD+の前駆体を増やすための薬理学的戦略は実現可能であり,心不全の治療に高い翻訳的可能性を秘めている.

キーワード:

心臓代謝心不全ハイパートロフィーミトコンドリア浸透性の移行孔

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