細胞DNAを感知することで,直接的なcGAMP依存PKGI活性化によって血圧を下げる

Jie Su¹, Pierre Coleman¹, Angeliki Ntorla¹

¹School of Cardiovascular and Metabolic Medicine & Sciences, King's College London; The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, United Kingdom.

Circulation

|August 7, 2023

まとめ

循環型GMP- AMP合成酵素 (cGAS) は,炎症と血圧の調節を結びつけるPKGIを活性化するcGAMPを生成する. この経路は血圧を下げて,セプシス誘発の低血圧と組織低血流を引き起こします.

科学分野:

心血管生物学
免疫学
分子医学

背景:

循環型GMP- AMP合成酵素 (cGAS) は炎症に関与する重要な細胞塩基DNAセンサーである.
DNAによるcGAS活性化により,2',3'-サイクルGMP-AMP (cGAMP) が生成され,インターフェロンと炎症性サイトカインの産生を刺激する.
この研究は,心血管の調節におけるcGAMPの新たな役割を調査しています.

研究の目的:

cGAMPが血圧調節に影響を与えるメカニズムを解明する.
炎症と心血管機能の交響におけるcGAMPの役割を決定する.
cGAMPによるPKGIの直接活性化を調査する.

主な方法:

cGASとcGAMPの活動を評価するために分子,細胞,生化学分析を使用した.
血管の反応を評価するために筋膜検査の実験を行いました
cGAMPの放出と吸収をELISAとトランスポーター識別を用いて測定した.
野生型とcGASのノックアウトマウスの血圧をテレメトリを用いて評価した.

主要な成果:

血管内皮におけるcGASによって生成されるcGAMPは,MRP1によって挤出され,体積調節アニオンチャネル経由で血管の滑らかな筋肉細胞に輸入される.
cGAMPはPKGIを直接活性化し,酸化窒素経路とは無関係に血管緩解を媒介する.
このPKGIの活性化は血圧を低下させ,血圧低下の原因となる.

結論:

cGAMP- PKGIの活性化により,cGASによる細胞塩基DNAの検出が血圧の調節につながります.
この経路は血圧低下と組織低血流を媒介するセプシスにおいて重要な役割を果たします
生まれつきの免疫と心血管のホメオスタシスを結びつける新しい信号軸を特定しました

キーワード:

血圧 cGASタンパク質マウス周期的なGMP依存タンパク質キナーゼサイクルグアノシン・モノフォスファート-アデノシン・モノフォスファートセプシス

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