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トロンボスポンディン-2の欠如は,年齢に関連した膨張性心筋病を引き起こす
Melissa Swinnen1, Davy Vanhoutte, Geert C Van Almen
1Center for Heart Failure Research, CARIM, Maastricht University, Maastricht, the Netherlands.
Circulation
|October 7, 2009
まとめ
高齢マウスのトランボスポンディン-2 (TSP-2) 欠乏症は,拡張性心筋病と死亡率の増加につながる. TSP-2の復元は心臓病を予防し,心臓の老化に対する保護的役割を強調する.
科学分野:
- 心血管生物学 心血管生物学
- 老化に関する研究
- マトリックス生物学 (Matrix Biology) とは
背景:
- 心臓の老化には,心臓の細胞外マトリックスに重大な変化が伴う.
- 年齢に関連した心臓の改造における,トロンボスポンディン-2 (TSP-2) のような母細胞タンパク質の役割は,完全に理解されていません.
研究 の 目的:
- 生理学的老化中の心臓の構造と機能に対するThrombospondin-2 (TSP-2) の影響を調査する.
- TSP-2欠乏が年齢依存性心疾患に寄与するかどうかを判断する.
主な方法:
- 60週までのTSP-2ノックアウト (KO) と野生型のマウスの比較.
- 生存率,心臓機能,形態学,超構造の評価.
- アデノ関連ウイルス-9を用いた遺伝子療法により,KOマウスにおけるTSP-2発現を回復する.
- マトリックス金属タンパク質酵素,トランスグルタミンゼ活性,およびコラーゲンクロスリンクの分析.
主要な成果:
- TSP-2KOマウスは生存率が著しく低下し,心筋機能障害と生理繊維症の増加による重度の拡張性心筋病を60週後に発症した.
- KOマウスにおける超構造分析は,筋細胞のストレス,死,炎症,線維症を明らかにしたが,血管系は変化しなかった.
- 若いKOマウスの遺伝子介在のTSP-2移植は生存率を正常化し,心筋病を予防しました.
- TSP-2欠乏症は,マトリックスメタルプロテインアゼ-2と組織トランスグルタミンアゼ-2の活性が変化し,コラーゲンのクロスリンクが低下し,心筋細胞におけるAkt生存経路の活性化が低下した.
結論:
- 心臓のTSP-2発現は,年齢依存の拡張性心筋病変から保護するために重要である.
- TSP-2は,老化中に心臓の完全性と機能を維持する上で重要な役割を果たします.
- TSP-2をターゲットにすることで,年齢関連の心臓病の治療戦略を提供することができる.
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