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.