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Guadalupe Villarreal, Jr., Thore Schmedt, Roberto Pineda, Ula V. Jurkunas; Evaluating the Use of Statins in the Establishment of a Corneal Endothelial Protective Phenotype. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5995.
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Oxidant-antioxidant imbalance has emerged as an important pathophysiological mechanism in Fuchs endothelial corneal dystrophy (FECD). Endothelial levels of nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcriptional mediator of anti-oxidant gene expression, are downregulated in patients with FECD. HMG-CoA reductase inhibitors, or statins, have been shown to confer anti-oxidant properties in part via the activation of Nrf2 expression. The purpose of this study was to determine whether statins could activate Nrf2 expression in human corneal endothelial cells, thereby inducing anti-oxidant transcriptional programs critical for the suppression of DNA damage.
An immortalized normal human corneal endothelial cell line (HCECi) was used for all experiments. HCECi were incubated with simvastatin for 24, 48, 72, and 96 h. HCECi were treated with varying doses of simvastatin, including 0.1, 0.5, 1.0, 5.0, and 10.0 µM. Quantitative real-time PCR was used to determine the effect of simvastatin on the expression of Nrf2 and its known downstream transcriptional target heme oxygenase 1 (HO-1).
No significant cellular toxicity was observed with 0.1, 0.5, or 1.0 µM simvastatin and DMSO control treatments. Incubation with 5.0 and 10.0 µM simvastatin resulted in significant cellular toxicity compared to respective DMSO control groups. Incubation of HCECi with varying doses of simvastatin for 24 h did not reveal any significant changes in Nrf2 mRNA expression (n=3). While HO-1 mRNA expression showed no significant changes following 0.1 and 0.5 µM simvastatin treatment (n=3), incubation with 1.0 µM simvastatin for 24 h resulted in an 18% decrease in HO-1 mRNA expression relative to DMSO control treatment (n=3, p=0.003). A time course experiment revealed 6%, 37%, and 5% decreases in HO-1 mRNA expression following 1.0 µM simvastatin treatment for 48, 72, and 96 h respectively (n=1).
The findings derived from this study did not demonstrate any significant changes in Nrf2 mRNA expression following simvastatin treatment. While the effect of simvastatin on HO-1 mRNA expression was statistically significant, the decrease was modest. Further studies are necessary to investigate the effect of simvastatin on apoptosis levels in normal HCECi as well as FECD tissue.
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