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Effects of simvastatin on the expression of heme oxygenase-1 in human RPE cells.
MedLine Citation:
PMID:  22918643     Owner:  NLM     Status:  MEDLINE    
PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Kyoung Jin Kim; Kyong Sil Kim; Na Rae Kim; Hee Seung Chin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-21
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  53     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-24     Completed Date:  2012-12-10     Revised Date:  2013-01-09    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6456-64     Citation Subset:  IM    
Department of Ophthalmology and Inha Vision Science Laboratory, Inha University School of Medicine, Incheon, Republic of Korea.
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MeSH Terms
Cell Survival / drug effects
Cells, Cultured
Free Radicals / metabolism
Gene Expression Regulation, Enzymologic / drug effects
Heme Oxygenase-1 / genetics*,  metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / toxicity
Oxidative Stress / drug effects
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Retinal Pigment Epithelium / cytology,  drug effects*,  enzymology*
Signal Transduction / drug effects
Simvastatin / toxicity*
Toxicity Tests / methods
Reg. No./Substance:
0/Free Radicals; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 79902-63-9/Simvastatin; EC protein, human; EC Oxygenase-1; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC protein, human; EC Proteins c-akt

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