ミトコンドリアの超酸化物産生を正常化することで,高血糖性損傷の3つの経路をブロックする

T Nishikawa¹, D Edelstein, X L Du

¹Albert Einstein College of Medicine, Diabetes Research Centre, Bronx, New York 10461, USA.

Nature

|April 28, 2000

まとめ

糖尿病性高血糖症は,ミトコンドリアの活性酸素種 (ROS) を増加させ,血管に損傷を与える. ROSの産生をターゲットにすることで,この高血糖ダメージに関与する重要な経路を防ぐことができます.

科学分野:

バイオケミストリーバイオケミストリー
細胞生物学細胞生物学
糖尿病学糖尿病学

背景:

糖尿病性高血糖症は,小血管,動脈,外周神経の病理的変化を引き起こす.
血管内皮細胞は,根底にあるメカニズムが不明な高血糖損傷の主要な標的である.
3つの主要な経路が関与しています:タンパク質キナーゼC (PKC) の活性化,高度なグリケーション最終産物 (AGEs) の形成,アルドース還元酵素経路の流動.

研究の目的:

ミトコンドリアの活性酸素種 (ROS) が血管内皮細胞に与える高血糖性損傷における役割を調査する.
ミトコンドリアのROSレベルを正常化させることで,重要な生化学経路の活性化を防ぐことができるかどうかを判断する.

主な方法:

高血糖状態に曝された,使用された培養牛の大動脈内皮細胞.
電子伝送連鎖複合体IIの阻害剤,酸化性リン酸化の解離剤,解離タンパク質-1およびマンガン超酸化物ディスミュータゼの投与.
ROSの生成,PKCの活性化,AGEの形成,ソービトールの蓄積,NF-kappaBの活性化への影響を評価した.

主要な成果:

高血糖症は,内皮細胞におけるROSの産生を増加させた.
ミトコンドリアのROS生成を標的とした阻害剤は,この増加を効果的に防ぐことができました.
ミトコンドリアのROS濃度の正常化は,グルコース誘発のPKC活性化,AGE形成,ソルビトール蓄積,NF-kappaB活性化を取り消した.

結論:

ミトコンドリアのROSは,血管内皮細胞における高血糖損傷の中心的な媒介者である.
ミトコンドリアのROS生成をターゲットにすることは,糖尿病の血管合併症に対する潜在的な治療戦略を提供します.

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