ニトロゼーティブ・ストレスは心不全を誘発し,エジェクション分子が保存される
Gabriele G Schiattarella1,2, Francisco Altamirano1, Dan Tong1
1Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|April 12, 2019
まとめ
発射分子が保存された心不全 (HFpEF) には効果的な治療法がない. 研究者らは,マウスの酸化窒素合成酵素を阻害することで,HFpEFを模倣し,心臓機能に不可欠なX-box-binding protein 1 (XBP1s) を含む経路を明らかにした.
科学分野:
- 心血管生物学
- 分子医学
- 病理生理学
背景:
- 発射分数保存 (HFpEF) による心不全は,高い罹病率と死亡率を伴う重大な臨床的課題です.
- HFpEFの現在の治療戦略は限られており,証拠に基づいた治療法がない.
研究 の 目的:
- HFpEFの背後にある分子メカニズムを調査する
- HFpEFの潜在的治療標的を特定する.
主な方法:
- 高脂肪食とN-ニトロ-L-アルギニンメチルエステル (L-NAME) を用いてマウスモデルを開発し,HFpEFを模倣して代謝および高血圧を誘発した.
- 発現したタンパク質反応エフェクタ X-box-binding protein 1 (XBP1s) の発現と機能を研究した.
- HFpEFの病原性における誘導性酸化窒素合成酵素 (iNOS) と IRE1α-XBP1経路の役割を調査した.
主要な成果:
- マウスモデルでは,ヒトのHFpEFの主要な全身的および心血管特性を成功裏に再現した.
- HFpEFマウスモデルとヒトの患者において,心筋XBP1sの発現の低下が観察された.
- iNOSの活性が増加し,その後のIRE1αのS- ニトロシル化により,XBP1のスペライシングが欠陥し,HFpEFのフェノタイプに寄与した.
- iNOSの抑制またはXBP1sの強化は,マウスモデルにおけるHFpEF現象型を改善した.
結論:
- iNOSによって誘導されるIRE1α- XBP1経路の調節不全は,HFpEFにおける心筋細胞機能障害に貢献する重要なメカニズムである.
- iNOS-IRE1α-XBP1経路をターゲットにすることで,HFpEFに対する新しい治療法を提供することができる.
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