NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence

Modesto Rojas; Tahira Lemtalsi; Haroldo A Toque; Zhimin Xu; David Fulton; Robert William Caldwell; Ruth B Caldwell

doi:10.3390/antiox6020043

NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence

Antioxidants (Basel). 2017 Jun 15;6(2):43. doi: 10.3390/antiox6020043.

Authors

Modesto Rojas^{1

2}, Tahira Lemtalsi^{3

4}, Haroldo A Toque⁵, Zhimin Xu^{6

7}, David Fulton^{8

9}, Robert William Caldwell¹⁰, Ruth B Caldwell^{11

12}

Affiliations

¹ Vascular Biology Center, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, USA. [email protected].
² VA Medical Center, One Freedom Way, Augusta, GA 30904-6285, USA. [email protected].
³ Vascular Biology Center, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, USA. [email protected].
⁴ VA Medical Center, One Freedom Way, Augusta, GA 30904-6285, USA. [email protected].
⁵ Department of Pharmacology & Toxicology, Augusta University, 1459 Laney Walker, Boulevard, Augusta, GA 30912-2500, USA. [email protected].
⁶ Vascular Biology Center, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, USA. [email protected].
⁷ VA Medical Center, One Freedom Way, Augusta, GA 30904-6285, USA. [email protected].
⁸ Vascular Biology Center, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, USA. [email protected].
⁹ Department of Pharmacology & Toxicology, Augusta University, 1459 Laney Walker, Boulevard, Augusta, GA 30912-2500, USA. [email protected].
¹⁰ Department of Pharmacology & Toxicology, Augusta University, 1459 Laney Walker, Boulevard, Augusta, GA 30912-2500, USA. [email protected].
¹¹ Vascular Biology Center, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912-2500, USA. [email protected].
¹² VA Medical Center, One Freedom Way, Augusta, GA 30904-6285, USA. [email protected].

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.

Keywords: NO; NOS; NOX2/NADPH oxidase 2; arginase 1; diabetic retinopathy; endothelial cell; oxidative stress; retina; senescence associated β-galactosidase.

Abstract

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