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J. Li, J. J. Wang, D. Chen, R. Mott, J.-X. Ma, S. X. Zhang; HMG-CoA Reductase Inhibitor Regulates Expression of Pro/Anti-Inflammatory Factors by Increase Anti-Oxidative Defense in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4914.
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3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are frequently used lipid-lowering drugs in type 2 diabetes. Recent emerging evidence suggests statins also possess anti-inflammatory activity and protect cardiovascular function. However, the potential role of statins in diabetic retinopathy is largely unclear. In present study we for the first time investigated the effect of lovastatin on regulating expression of pro/anti-inflammatory factors in the retina of db/db mice and in retinal vascular endothelial cells and explored the possible mechanisms.
Male C57BLKS/J db/db mice and primary bovine retinal capillary endothelial cells (RCEC) were used in this study. At 13 weeks of age, db/db mice were randomly chosen to receive 10 mg/kg lovastatin or vehicle control (6-8 mice in each group) via gavage daily. After 6 weeks of treatment, the mice were euthanized, and retinas dissected. Bovine RCEC were treated with lovastatin (1-10 µM) in normal glucose (5 mM) or high glucose (25 mM) medium or under hypoxia (2% oxygen) condition for 24 h. Expression of pro/anti-inflammatory factors, tight junctional proteins and anti-oxidative enzymes in the retinas and in the cells were determined by Western blot analysis.
Expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) were increased and expression of zonula occludens-1 (ZO-1), occludin, and pigment epithelium derived factor (PEDF) in the retina were decreased in db/db mice when compared to age-matched controls. Treatment with lovastatin decreased ICAM-1 and VEGF expression and increased occludin and ZO-1 expression in the retina of db/db mice. In cultured RCEC, lovastatin significantly up-regulated PEDF expression in a dose-dependent manner. Moreover, lovastatin decreased VEGF expression and increased PEDF expression in high glucose-exposed RCECs. Further mechanistic study demonstrated that lovastatin significantly up-regulated superoxide dismutase 2 (SOD2) expression in RCECs under normal, high glucose and hypoxia conditions.
The results from this study established a protective role of lovastatin on the blood-retinal barrier, which is at least in part mediated by down-regulation of pro-inflammatory factors and up-regulation of anti-inflammatory factors in the retina. Up-regulation of anti-oxidative defense by lovastatin is a potential mechanism responsible its beneficial effects on anti-inflammation and blood-retina barrier in diabetic retinopathy.
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