Rojas Modesto, Lemtalsi Tahira, Toque Haroldo A, Xu Zhimin, Fulton David, Caldwell Robert William, Caldwell Ruth B
Vascular Biology Center, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, USA.
VA Medical Center, One Freedom Way, Augusta, GA 30904-6285, USA.
Antioxidants (Basel). 2017 Jun 15;6(2):43. doi: 10.3390/antiox6020043.
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.
活性氧（ROS）增加和一氧化氮（NO）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以及增加与一氧化氮合酶（NOS）竞争共同底物L-精氨酸的精氨酸酶活性来降低NO。ROS增加和NO减少可导致内皮细胞（EC）过早衰老，从而导致血管修复缺陷。我们之前已经证明了NADPH氧化酶2（NOX2）衍生的ROS、NO减少和精氨酸酶过度活跃在DR中的作用。在此，我们研究了它们对糖尿病诱导的EC衰老的影响。使用糖尿病小鼠和用高糖或H₂O₂处理的视网膜ECs的研究表明，ROS形成增加、精氨酸酶表达和活性升高以及NO形成减少导致EC过早衰老。阻断NOX2或抑制精氨酸酶可防止这些影响。抑制NOS活性也会增加EC衰老，而用NO供体治疗可防止这种情况。这些结果表明，糖尿病/高糖诱导的精氨酸酶激活和NO生物利用度降低会加速EC衰老。NOX2产生的ROS在这一过程中起重要作用。阻断NOX2或精氨酸酶是一种通过保持NO生物利用度来预防糖尿病诱导的EC过早衰老的策略。
