Role of NADPH Oxidase and STAT3 in Statin-mediated Protection Against Diabetic Retinopathy

¹ Oral Biology, Medical College of Georgia, Augusta, Georgia, United States
² Ophthalmology, University of South Carolina, Columbia, South Carolina, United States
³ College of Pharmacy, University of Georgia, Augusta, Georgia, United States
⁴ Pharmacology, Medical College of Georgia, Augusta, Georgia, United States
⁵ Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, United States
⁶ Vascular Biology Center, Medical College of Georgia, 1120 15 St, Augusta, Georgia, 30912, United States

^* To whom correspondence should be addressed. E-mail: rcaldwel{at}mail.mcg.edu.

	Abstract

Purpose. Inhibitors of 3-Hydroxy-3-methylglutaryl CoA reductase, statins, reduce signs of diabetic retinopathy in diabetic patients and animals. Indirect clinical evidence supports the actions of statins in improving cardiovascular function, but the mechanisms of their protective actions in the retina are not understood. Our studies have implicated oxidative stress and NADPH oxidase-mediated activation of signal transducer and activator of transcription 3 (STAT3) in diabetes-induced increases in expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) and breakdown of the blood-retinal barrier. Because statins are known to have potent antioxidant actions, we hypothesized that the protective effects of statins in preventing diabetic retinopathy involve blockade of diabetes-induced activation of NADPH oxidase and STAT3. Methods. We tested this hypothesis by experiments using streptozotocin-induced diabetic rats and high glucose-treated retinal endothelial cells treated with simvastatin. Blood-retinal barrier function was assayed by determining extravasation of albumin. Oxidative stress was assayed by measuring lipid peroxidation, protein nitration on tyrosine, dihydroethidine oxidation and chemilumenescence. Immunoprobe techniques were used to determine levels of NADPH oxidase subunit expression and STAT3 activation. Results. These studies showed that simvastatin blocks diabetes or high glucose-induced increases in VEGF and ICAM-1 and preserves the blood-retinal barrier (BRB) by a process involving blockade of diabetes/high glucose-induced activation of STAT3 and NADPH oxidase. Statin treatment also prevents diabetes-induced increases in expression of the NADPH oxidase catalytic and subunit NOX2. Conclusion. These results suggest that simvastatin protects against the early signs of diabetic retinopathy by preventing NADPH oxidase-mediated activation of STAT3

Key Words: diabetic retinopathy, blood-retinal barrier, cell culture, growth factors, oxidative damage

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