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局所性ペロキシニトリートは,内皮の臨時受容体潜在バニロイド4チャンネルを損ない,肥満における血圧を上昇させる

Matteo Ottolini^1,2, Kwangseok Hong¹, Eric L Cope¹

¹Robert M. Berne Cardiovascular Research Center (M.O., K.H., E.L.C., Z.D., L.J.D., C.M., N.Y.N., S.R.J., B.E.I., S.K.S.).

|February 4, 2020

まとめ

肥満は内皮のTRPV4チャネル活性を低下させることで血圧の調節を阻害し,これはペロキシニートによるAKAP150の損傷に関連している. ペロキシニトリトを抑制すると,肥満患者の正常な血圧と血管拡張が回復します.

科学分野:

心血管の生理学
内皮細胞生物学
高血圧研究

背景:

内皮に依存する血管拡張は血圧の調節に不可欠であり,肥満による高血圧では低下する.
トランジエント・レセプター・ポテンシャル・バニロイド4 (TRPV4) チャンネルは,内皮カルシウムシグナル伝達と血管拡張の鍵です.
AKAP150タンパク質はTRPV4チャネル活性を増強しますが,肥満に関連する高血圧におけるその役割は不明です.

研究の目的:

肥満における血圧調節における内皮AKAP150-TRPV4信号伝達の役割を調査する.
肥満患者でこの信号伝達経路が損なわれるかどうかを判断するためです
ペロキシニート抑制の治療的可能性を評価する

主な方法:

内皮特異的なノックアウトと高脂肪食による肥満マウスモデルを使用した.
AKAP150- TRPV4のシグナル伝達と血管拡張に対するペロキシニトリートの影響を評価した.
臨床的関連性を評価するために,ヒトの動脈を検査した.

主要な成果:

肥満はTRPV4チャネルの血圧低下効果を低下させた.
肥満マウスのTRPV4活性と血管拡張を逆説的に弱めた.
ペロキシニトリートは,AKAP150をCys36で酸化し,AKAP150-TRPV4のシグナル伝達と血管拡張を阻害した.
ペロキシニート濃度を下げることで信号伝達,血管拡張,肥満における血圧を回復させました
肥満患者の動脈にも同様のペロキシニート依存性障害が認められた.

結論:

肥満に起因する高血圧に寄与する.
ペロキシニートによるAKAP150の損傷は重要なメカニズムです.
ペロキシニトリトを抑制すると,内皮機能が回復し,肥満では血圧が正常化します.

キーワード:

カルシウム信号エンドセリウム高血圧イオンチャネル窒素酸化物ペロキシニート

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