核受容体NR1D1は,ミトコンドリア三炭酸循環酵素アコニタゼ-2を標的として,腹動脈動脈瘤の発達を調節する

Ling-Yue Sun¹, Yu-Yan Lyu¹, Heng-Yuan Zhang¹

¹State Key Laboratory for Oncogenes and Related Genes, Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (L.-Y.S., Y.-Y.L., H.-Y.Z., Z.S., G.-Q.L., N.G., Z.-H.F., X.G., N.L., S.D., A.-C.Y., J.P.).

|July 26, 2022

まとめ

核受容体NR1D1は,血管の滑らかな筋肉細胞のミトコンドリア代謝を調節することによって,腹部大動脈瘤 (AAA) の発現に重要な役割を果たします. アルファケトグルタレート (αKG) の補充は,AAAに対する新しい治療戦略を提供することができる.

科学分野:

分子生物学
心血管研究
代謝障害

背景:

代謝障害は腹動脈動脈瘤 (AAA) の重要なリスク因子です.
核受容体 (NRs) は細胞代謝を調節するが,AAAの病原性におけるその役割は不明である.
NR1D1はAAA組織で高度にアップレギュレーションされたNRとして識別されます.

研究の目的:

腹動脈動脈瘤 (AAA) の発生におけるNR1D1の役割を調査する.
NR1D1がAAA形成に影響を与える分子メカニズムを解明する.
NR1D1経路を標的とした治療戦略を探求する.

主な方法:

AAA組織におけるNRスーパーファミリーの発現を分析した.
AngIIおよびCaPO4誘発のAAAモデルでは,細胞特有の条件付きノックアウトマウス (VSMC,内皮,骨髄) を利用した.
NR1D1- ACO2の相互作用とミトコンドリアの代謝への影響を研究した.

主要な成果:

NR1D1はAAA組織とVSMCにおいて著しく上位調節された.
VSMC のノックアウトは,他の細胞タイプではなく,AAA形成を阻害しました.
NR1D1はACO2を直接抑制し,ミトコンドリアの代謝に影響を与え,αKGの補給は治療効果を示した.

結論:

NR1D1は,VSMCにおけるNR1D1-ACO2軸を通じたAAA病原性の新しい調節剤である.
NR1D1はミトコンドリアの代謝を調節し,AAAの発達に寄与する.
アルファケトグルタレート (αKG) のサプリメントは,AAAに対する有望な治療法です.

キーワード:

腹部アオルタ動脈瘤アルファ・ケトグルタレートミトコンドリア核受容体血管の滑らかな筋肉

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