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Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
プロリルヒドロキシラーゼドメインタンパク質の抑制は,治療的再血管化を促進する
Céline Loinard1, Amandine Ginouvès, José Vilar
1Paris Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, Université Paris 5, Paris, France.
Circulation
|June 24, 2009
まとめ
プロリルヒドロキシラーゼドメインタンパク質 (PHDs),特にPHD3を阻害すると,低酸素誘導因子1 (HIF-1) を上昇調節することにより,治療的再血管化を強化します. この研究では,HIF-1シグナル伝達が,イシュケミアの後の血管成長を促進するために重要であることが確認されています.
科学分野:
- 分子生物学は分子生物学である.
- 血管生物学 血管生物学
- イシュケミア 研究 イシュケミア 研究
背景:
- 低酸素誘導因子 (HIF) のサブユニットは,酸素に依存するプロリルヒドロキシラーゼドメインタンパク質 (PHD) によって調節されます.
- PHDs (PHD1,PHD2,PHD3) は,HIFを対象に劣化させています.
- PHD抑制を研究して,HIFを高調調節して,後発血性新血管化を促進する.
研究 の 目的:
- HIFアップレギュレーションによるPHDの抑制が,後発血性新血管化を促進するかどうかを判断する.
- このプロセスにおける特定のPHD同型 (PHD1,PHD2,PHD3) の役割を評価する.
- HIF-1シグナリングがプロ血管新生効果を媒介する必要性を確認する.
主な方法:
- ネズミは右股関節動脈の縛り手術を受けた.
- HIF-1alpha,PHD1,PHD2,またはPHD3.3を標的とした短いヘアピンRNA (shRNA) のインビボ電子伝達.
- 対照群は,無関係なshRNA (shCON) を受けた.
- PHDs,HIF-1alpha,VEGF-A,eNOS,MCP-1,およびマクロファージの浸透のmRNAおよびタンパク質レベルの分析.
- 新血管化と足の perfusion の評価.
主要な成果:
- PHDs (特にPHD2とPHD3) を静止させると,一時的にPHD mRNA/タンパク質をダウンレギュレーションし,HIF-1alpha.をアップレギュレーションします.
- プロ血管新生因子 (VEGF-A,eNOS) の増調とマクロファージの浸透の強化 (shPHD2/shPHD3による).
- shPHD2およびshPHD3で治療されたマウスの血管密度,毛細血管密度,足の perfusion の有意な増加.
- shHIF-1alphaの併用はshPHD3の効果を無効化し,HIF-1依存性を確認した.
結論:
- PHDs,特にPHD3の直接的抑制は,治療的再血管化を促進する.
- HIF-1シグナリング経路は,PHDサイレンシングのプロ血管新生効果を媒介するために不可欠です.
- PHDをターゲットにすることは,不血性疾患の治療のための潜在的な戦略です.
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