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Kyoung Jin Kim, Kyong Sil Kim, Na Rae Kim, Hee Seung Chin; Effects of Simvastatin on the Expression of Heme Oxygenase-1 in Human RPE Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(10):6456-6464. doi: https://doi.org/10.1167/iovs.12-9658.
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Chronic oxidative stress can lead to the impairment of RPE cells, indicating it to be a risk factor for AMD. The cholesterol-independent, pleiotropic effects of statins have protective effects on several cell types via unknown mechanisms. This study examined the role of heme oxygenase-1 (HO-1) as a target and potential mediator of statins in cultured human RPE cells.
The RPE cell viability was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. After 24 hours incubation, RT-PCR and Western blot was performed to measure the levels of HO-1 mRNA and protein expression, respectively, in RPE cells. Intracellular reactive oxygen species (ROS) production was measured using a fluorescence-activated cell sorter.
In cultured human RPE cells, simvastatin showed no toxicity up to 10 μM. Simvastatin increased the HO-1 mRNA and protein levels in a concentration-dependent manner up to 10 μM. HO-1 protein induction by simvastatin was unaffected by mevalonate or N-nitro-L-arginine methyl ester, showing that the isoprenoid- and NO-dependent pathways are not involved. Simvastatin-dependent HO-1 protein induction was reduced significantly by pharmacological inhibition of the phosphotidylinositol-3-kinase (PI3K)/Akt pathways. The simvastatin-induced inhibition of free radical formation was recovered by the presence of an HO inhibitor, zinc protoporphyrin.
These results demonstrate that HO-1 is a target site and an antioxidant mediator of simvastatin in human RPE cells. Simvastatin-dependent upregulation of HO-1 is mainly via PI3K/Akt-dependent signaling pathways. Simvastatin may have some clinical benefits in preventing retinal diseases associated with oxidative stress, such as AMD.
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