血管損傷後のネオインティマ形成におけるp38ミトゲン活性化タンパク質キナーゼ活性に対する要件
Brandon M Proctor1, Xiaohua Jin, Traian S Lupu
1Center for Cardiovascular Research, Department of Medicine, Washington University, St. Louis, School of Medicine, ST. Louis, Mo., USA.
Circulation
|July 23, 2008
まとめ
血管の滑らかな筋肉細胞p38alpha MAPKの活性化は,血管新生手術後のネオインティマル病変の形成に不可欠です. この経路を阻害すると,病変の発生を防止し,関連する細胞増殖とDNA複製を減少させます.
科学分野:
- 心血管生物学 心血管生物学
- 分子医学は分子医学である.
- 血管細胞生物学 血管細胞生物学
背景:
- アンジオプラスティとステントは,動脈硬化性血管疾患の合併症であるネオインティマル病変の形成につながる可能性があります.
- 成長因子受容体結合タンパク質2 (Grb2) は,ネオインティマの形成と血管の滑らかな筋肉細胞 (SMC) のp38 MAPKの活性化に不可欠です.
- ネオインティマルの発達における血管SMC p38alpha MAPKの特定の役割については,さらなる調査が必要である.
研究 の 目的:
- ネオインティマル病変の発生における血管SMC p38alpha MAPKの役割を調査する.
- p38alpha MAPKがネオインティマ形成に寄与する分子メカニズムを解明する.
主な方法:
- ドキシサイクリン誘導性SMC特異的な支配的負のp38alpha MAPK (DN-p38alpha) の発現を持つ合成トランスジェニックマウスを生成した.
- DN-p38alpha発現を誘発するためにドキシサイクリンを投与し,頸動脈損傷後のネオインティマ形成を評価した.
- SMC増殖および関連する分子イベントに対するp38alpha MAPK阻害 (SB202190またはsiRNA) の影響を調査するために,インビトロSMC培養システムを利用しました.
主要な成果:
- ドキシサイクリン治療は,トランス遺伝子マウス動脈におけるDN-p38alpha発現を成功裏に誘導した.
- ドキシサイクリンを投与されたマウスは,ネオインティマ形成に対する耐性を示し,頸動脈損傷後にp38 MAPKの活性化が低下した.
- 培養SMCにおけるp38alpha MAPKの阻害は,血小板由来成長因子誘発の増殖,DNA複製,網膜母細胞タンパク質のリン酸化,およびミニクロモソーム維持タンパク質6誘導を阻害した.
結論:
- 血管SMC p38alpha MAPKの活性化は,ネオインティマル病変の形成に不可欠な要素である.
- p38alpha MAPKは,レチノブラストームタンパク質のリン酸化とミニクロモソーム維持タンパク質6の発現を促進することによって,ネオインティマの形成を促進する可能性が高い.
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