NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence.
NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence.
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DOI：
10.3390/antiox6020043
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发表时间：
2017-06-15
期刊：
影响因子：
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通讯作者：
Caldwell RB
中科院分区：
文献类型：
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作者：
Rojas M;Lemtalsi T;Toque HA;Xu Z;Fulton D;Caldwell RW;Caldwell RB
活性氧（ROS）的增加和一氧化氮（NO）的减少与糖尿病视网膜病变（DR）期间的血管功能障碍有关。糖尿病可通过增加ROS和增加与一氧化氮合酶（NOS）竞争其共同底物L-精氨酸的精氨酸酶的活性来减少NO。增加的ROS和减少的NO可引起过早的内皮细胞（EC）衰老，导致缺陷的血管修复。我们以前已经证明了参与NADPH氧化酶2（NOX 2）衍生的ROS，减少NO和过度活跃的DR中，在这里，我们研究了它们对糖尿病诱导的EC衰老的影响。使用糖尿病小鼠和高葡萄糖或H2 O2处理的视网膜EC的研究表明，ROS形成的增加，升高的葡萄糖氧化酶表达和活性，以及NO形成的减少导致过早的EC衰老。阻断NOX 2或抑制腺苷酸酶可防止这些作用。EC衰老也增加了抑制NOS活性，这是防止治疗与NO供体。这些结果表明，糖尿病/高葡萄糖诱导的β-淀粉酶的激活和NO生物利用度的降低加速EC衰老。NOX 2产生的ROS对这一过程有重要贡献。阻断NOX 2或NOS代表了通过保持NO生物利用度来预防糖尿病诱导的EC过早衰老的策略。
Increases in reactive oxygen species (ROS) and decreases in nitric oxide (NO) have been linked to vascular dysfunction during diabetic retinopathy (DR). Diabetes can reduce NO by increasing ROS and by increasing activity of arginase, which competes with nitric oxide synthase (NOS) for their commons substrate l-arginine. Increased ROS and decreased NO can cause premature endothelial cell (EC) senescence leading to defective vascular repair. We have previously demonstrated the involvement of NADPH oxidase 2 (NOX2)-derived ROS, decreased NO and overactive arginase in DR. Here, we investigated their impact on diabetes-induced EC senescence. Studies using diabetic mice and retinal ECs treated with high glucose or H2O2 showed that increases in ROS formation, elevated arginase expression and activity, and decreased NO formation led to premature EC senescence. NOX2 blockade or arginase inhibition prevented these effects. EC senescence was also increased by inhibition of NOS activity and this was prevented by treatment with a NO donor. These results indicate that diabetes/high glucose-induced activation of arginase and decreases in NO bioavailability accelerate EC senescence. NOX2-generated ROS contribute importantly to this process. Blockade of NOX2 or arginase represents a strategy to prevent diabetes-induced premature EC senescence by preserving NO bioavailability.