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H19 腹動脈動脈瘤の発達と進行を誘発する
Daniel Y Li1, Albert Busch1, Hong Jin2
1Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar (D.Y.L., A. Busch, J.P., S.L., H.-H.E., L.M.), Technical University Munich, and German Center for Cardiovascular Research (DZHK), partner site Munich, Germany.
Circulation
|April 20, 2018
まとめ
長い非コーディングRNAH19は,腹動脈動脈瘤の発達における滑らかな筋肉細胞の生存を調節する. H19を阻害することは,大動脈動脈瘤の病気に対する新しい治療戦略を提供するかもしれません.
科学分野:
- 分子生物学
- 遺伝学
- 心血管研究
背景:
- 長い非コーディングRNA (lncRNAs) は,生物学的プロセスと疾患における重要な調節因子である.
- 腹動脈動脈瘤 (AAA) の発症には複雑な分子メカニズムが伴う.
- AAAの病原性における新しいlncRNAを特定することは,治療開発にとって極めて重要です.
研究 の 目的:
- 腹動脈動脈瘤 (AAA) 発現に関与する lncRNA を識別し,機能的に特徴づける.
- AAAの病原性における lncRNA H19の役割を調査する.
- H19をAAAの 治療対象として検討する
主な方法:
- 2つのマウンのAAAモデルにおけるRNAトランスクリプト発現のプロファイリング (アニオテンシンII注入と豚の臓エラスタゼ挿入).
- 定量的逆転写ポリメラーゼ連鎖反応と,H19発現を確認するための in situ 混合化.
- H19のノックダウンと滑らかな筋肉細胞 (SMC) の過剰発現のために,アンチセンセスオリゴヌクレオチド (LNA-GapmeRs) を用いたin vivoおよびin vitro実験.
- 低酸素誘導因子1α (HIF-1α) とp53を含むH19の下流効果因子の分析
主要な成果:
- 両方のマウンのAAAモデルでは, lncRNA H19が著しく上位調節された.
- H19の実験的なノックダウンにより,動脈瘤の成長とSMCのアポトーシスが vivoで減少した.
- H19過剰発現は,miR-675とは独立して,SMCアポトーシスをインビトロで増加させた.
- H19は細胞質のHIF- 1αと相互作用し,p53の安定化とSMCアポトーシスの増加につながります.
- H19は,特異性タンパク質1を勧誘することによって,HIF-1αの転写を促進する.
結論:
- lncRNA H19は,腹動脈動脈瘤の発達と進行におけるSMC生存とアポトーシスの新しい調節剤です.
- H19はAAAの病原性において重要な役割を果たします.
- H19の阻害は,大動脈動脈瘤の病気に対する新たな分子治療戦略を表しています.
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