Abstract
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.
Highlights
Diabetic retinopathy (DR) is a major cause of vision loss and blindness in working age adults [1].DR affects all retinal cells, especially the microvasculature [2,3]
We investigated the effects of diabetes-induced increases in NADPH oxidase 2 (NOX2)-NADPH oxidase
We found that diabetes- or high glucose-induced increases in NOX2/NADPH-generated reactive oxygen species (ROS) induce formation
Summary
Diabetic retinopathy (DR) is a major cause of vision loss and blindness in working age adults [1].DR affects all retinal cells, especially the microvasculature [2,3]. Diabetic retinopathy (DR) is a major cause of vision loss and blindness in working age adults [1]. Vision loss can occur due to macular edema, proliferative neovascularization or retinal neurodegeneration [4,5]. Microvascular changes in the diabetic retina, including leukostasis and increased vascular permeability, have been linked to increased formation of reactive oxygen species (ROS) [6,7]. Studies in a variety of tissues have shown that proper vascular function depends on appropriate basal production of nitric oxide (NO) and that NO function as an endothelial-derived vasodilator and anti-inflammatory factor is compromised in diabetes [8]. Diabetes can decrease NO bioavailability by several mechanisms, including increased production of superoxide. Superoxide will react rapidly with NO to form peroxynitrite. Peroxynitrite and other oxidants can cause NOS uncoupling due to oxidation of Antioxidants 2017, 6, 43; doi:10.3390/antiox6020043 www.mdpi.com/journal/antioxidants
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