p90RSK-NRF2シグナリングによって誘発される老化型は,HIV陽性個体における酸化ストレスに対するモノサイトとマクロファージを感受性化する
Meera V Singh1, Sivareddy Kotla2,3, Nhat-Tu Le2,4,3
1Departments of Microbiology and Immunology (M.V.S., N.E.S., K.J.G., S.B.M.), University of Rochester, NY.
Circulation
|December 28, 2018
まとめ
併用抗レトロウイルス療法 (cART) は,p90RSKを活性化させることで,マクロファージの老化と動脈硬化を引き起こすため,HIV陽性患者の心血管疾患のリスクを高めます. 単細胞/マクロファージのp90RSKを標的とした治療は,これらの患者の心血管合併症を予防することができます.
科学分野:
- 心血管科学
- 免疫学
- 分子生物学
背景:
- 心血管疾患 (CVD) の発生率は,HIV陽性 (HIV+) の個体では,一般集団と比較して高くなっています.
- 併用抗レトロウイルス療法 (cART) は,HIV+患者におけるCVDの既知の危険因子ですが,その基礎となる分子メカニズムは不明です.
研究 の 目的:
- HIV+患者におけるcART誘発のマクロファージの老化および加速されたアテロゲネシスにおけるp90RSK活性化の役割を調査する.
- cART,p90RSK,および心血管疾患の発症の間の分子関係を調査する.
主な方法:
- cART治療を受けたHIV+および未治療のHIV陰性個体におけるp90RSK活性を評価した.
- 頸動脈のプラーク形成,マクロファージの老化マーカー,p90RSK-NRF2の信号伝達経路を分析した.
- p90RSK阻害剤と活性化剤を使用し,骨髄細胞特異的変異性マウスの研究を行いました.
主要な成果:
- cARTを受けたHIV+患者は,p90RSKの活性と反応性酸素種に対する単細胞の感受性が高かった.
- cARTとp90RSKの基礎活性がプラーク形成の重要な決定因子であった.
- cARTはマクロファージの老化を誘発し,p90RSK媒介のERK5リン酸化によってNRF2- AREの活性を抑制し,NRF2の活性化はこれらの効果を相殺した.
結論:
- cARTは,p90RSKを介してNRF2- AREの活性を抑制することで,HIV+患者におけるモノサイト/ マクロファージの老化と炎症を促進する.
- 単細胞/マクロファージのp90RSK調節は,cART治療を受けたHIV+患者の心血管疾患を予防するための潜在的な治療目標です.
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