オートファギーから脱出するミトコンドリアDNAは,炎症と心不全を引き起こす
Takafumi Oka1, Shungo Hikoso, Osamu Yamaguchi
1Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Nature
|April 27, 2012
まとめ
ミトコンドリアDNAがオートファギーから脱出すると,心臓細胞の炎症を引き起こし,心不全を引き起こします. トール型受容体9 (TLR9) を阻害すると,この炎症反応を予防し,心臓損傷から保護します.
科学分野:
- 心血管生物学 心血管生物学
- 免疫学 免疫学とは
- 細胞生物学 細胞生物学
背景:
- 心不全は主要な死因であり,炎症がその発症に重要な役割を果たしています.
- 心臓の炎症を引き起こす正確なメカニズムは完全に理解されていません.
- 細菌から生まれたミトコンドリアには,免疫反応を誘発する可能性があるDNAが含まれています.
研究 の 目的:
- 心筋細胞内の炎症反応を開始するミトコンドリアDNAの役割を調査する.
- 損傷したミトコンドリアが心不全の病原化に寄与するメカニズムを解明する.
- 炎症に起因する心臓病の潜在的治療標的を調査する.
主な方法:
- リゾソーマルデオキシリボヌクレアゼII (DNase) の心臓特異的なデリエーションを有するマウスを研究した.
- 心臓のストレスを模倣するために誘導された圧力過負荷.
- トール型受容体9 (TLR9) に対して投与された抑制性オリゴデオキシヌクレオチド.
- 炎症マーカー,サイトカイン発現,心臓ヒストロジを分析した.
主要な成果:
- ミトコンドリアDNAがオートファギーから脱出すると,トール型受容体9 (TLR9) 媒介の炎症が誘発され,心筋炎と拡張性心筋病気が起こります.
- DNase II欠乏症が悪化すると,圧力の過負荷によって引き起こされる心不全があり,炎症とミトコンドリアDNAの蓄積が特徴です.
- DNase II欠乏症および野生型マウスにおけるTLR9弱化性心臓炎症および機能障害の抑制または消去.
結論:
- 損傷したミトコンドリアからのミトコンドリアDNAの放出は,心臓のTLR9依存性炎症の主要なトリガーです.
- DNase IIはミトコンドリアDNAをクリアする上で重要な役割を果たし,オートリソソームの蓄積とその後の炎症を予防します.
- TLR9を標的にすることは,炎症性心不全の潜在的な治療戦略を提供します.
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