骨形態遺伝タンパク質9は,心筋線維症を軽減し,心不全における心機能を改善する
Kevin J Morine1, Xiaoying Qiao1, Sam York1
1Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA.
Circulation
|March 1, 2018
まとめ
骨形態遺伝タンパク質9 (BMP9) は,Smad1を活性化することで,心不全における心筋線維症を抑制する. 心不全患者の治療戦略を提示する.
科学分野:
- 心血管生物学
- 分子医学
- 繊維症の研究
背景:
- 心不全は世界的な健康問題です
- 変形成長因子β (TGF-β1) は心臓線維症を誘発するが,逆調節経路によって調節される.
- TGF-βファミリーのメンバーである骨形態遺伝タンパク質9 (BMP9) はSmad1経由で信号を送り,TGF-β共受容体であるエンドグリンはBMP9と結合し,Smad3の信号伝達を促進する.
研究 の 目的:
- 心筋線維症におけるBMP9の役割を調査する.
- BMP9がSmad1とSmad3経路を調節することによって心臓線維症を抑制するかどうかを判断する.
- BMP9の活性を増強するかどうかを調べる.
主な方法:
- 人間の心筋線維芽細胞と心不全患者のBMP9発現を調べた.
- リコンビネントBMP9と小型の干渉RNAをヒトの心臓線維芽細胞で利用した.
- 心不全のマウスモデルを 採用した.
- 再結合BMP9を投与し,エンドグリン中和を in vivoと in vitroでテストした.
主要な成果:
- BMP9の発現は,心不全患者および心筋線維芽細胞で上昇しています.
- BMP9は心臓の線維細胞におけるコラーゲン合成を弱める.
- BMP9の喪失は心筋線維症を悪化させ,マウスの LV機能を損なう.
- BMP9治療は線維症を抑制し,心臓の機能を改善し,psmad1レベルを上昇させます.
- 中和するエンドグリンはBMP9の活性を高め,線維症を軽減し,psmad1を増加させます.
結論:
- BMP9は圧力の過剰に反応する内生性線維症阻害剤として作用する.
- 再結合BMP9またはエンドグリン中和はBMP9の活性を促進し,心臓線維症を抑制する.
- これらの発見は 心不全の管理のための新しい治療法を示唆しています
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