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アンジオテンシンII誘発の心筋縮および高血圧は,表皮成長因子受容体アンチセンセによって弱まります

Shuntaro Kagiyama¹, Satoru Eguchi, Gerald D Frank

¹Department of Physiology and Functional Genomics, University of Florida, Gainesville 32610-0274, USA.

|August 21, 2002

まとめ

アンジオテンシンII (Ang II) は,表皮成長因子受容体 (EGFR) を活性化することによって,左心室高縮症 (LVH) を引き起こす. EGFRをアンチセンセスのオリゴデオキシヌクレオチド (ASO) で抑制すると,Ang II誘発のLVHが効果的に減少し,ネズミの血圧が低下しました.

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.
細胞シグナル伝達細胞信号伝達

背景:

アンジオテンシンII (Ang II) は強力な血管収縮剤であり,心血管再建に関与する成長因子です.
Ang IIは1型受容体を通して信号を送るが,ミトーシスの開始に必要な固有のチロシンキナーゼ活性がない.
以前の研究によると,Ang IIは表皮成長因子受容体 (EGFR) 信号伝達を活性化させ,血管の滑らかな筋肉細胞 (VSMC) でチロシンキナーゼとERKの活性化につながる.

研究の目的:

Ang II誘発の左心室縮 (LVH) を媒介するEGFRの役割を調査する.
アンチセンセスのオリゴデオキシヌクレオチド (ASO) を用いてEGFRを抑制する効果を評価し,Ang II駆動の心血管効果を弱める.

主な方法:

培養VSMCでEGFR特異のアンチセンセスオリゴデオキシヌクレオチド (EGFR-AS) を開発および検証し,Ang II誘発のERKリン酸化を抑制しました.
Ang IIを注入した高血圧のラットにEGFR-ASを静脈内投与し,血圧 (BP),高血圧 (LVH),心臓EGFR発現/ERKリン酸化への影響を評価した.

主要な成果:

EGFR-ASは,EGFRの発現を成功裏に低下させ,VSMCにおけるAng II誘発のERKリン酸化を抑制しました.
In vivo,Ang II輸液はBPを大幅に増加させ,LVH (左心室/体重比の増加) を誘導した.
EGFR-AS治療は,LVHを正常化し,Ang II誘発EGFR発現とERKリン酸化を弱め,ラットでは高血圧を低下させた.

結論:

Epidermal成長因子受容体 (EGFR) は,血管の滑らかな筋肉細胞と心臓におけるアニオテンシンII (Ang II) 媒介のERK活性化に不可欠である.
EGFRは,Ang II誘発の左心室縮症 (LVH) の発症に重要な役割を果たしています.

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