ToxSci Advance Access originally published online on December 10, 2007
Toxicological Sciences 2008 102(1):150-159; doi:10.1093/toxsci/kfm298
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Statin-Induced Heme Oxygenase-1 Increases NF-
B Activation and Oxygen Radical Production in Cultured Neuronal Cells Exposed to Lipopolysaccharide
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* Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan
Department of Plastic and Reconstructive Surgery
Department of Neurosurgery
Department of Neurology, Chang Gung Memorial Hospital—Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan
1 To whom correspondence should be addressed at Department of Neurology, Chang Gung Memorial Hospital—Kaohsiung Medical Center, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien, Taiwan. Fax: +886-7-07-7328828. E-mail: m93chinghua{at}gmail.com.
Received October 29, 2007; accepted December 5, 2007
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Abstract |
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With potentially neuroprotective properties, heme oxygenase-1 (HO-1) has been suggested to be the main mediator of cholesterol-independent anti-inflammatory and antioxidant actions of statins. However, we had demonstrated that simvastatin-induced HO-1 increased apoptosis of Neuro 2A cells in glucose deprivation, and iron production from HO-1 activity may be responsible for the toxicity. This study was designed to explore the effect of simvastatin-induced HO-1 on cultured Neuro 2A and C6 cells exposed to lipopolysaccharide (LPS). We found that the HO-1 upregulation was significantly associated with increased nuclear factor kappa B (NF-
B) activation, manifested as IB
phosphorylation and p65 nuclear translocation, as well as increased production of superoxides. Inhibition of the induced HO-1 by zinc protoporphyrin reduced the increased NF-B activation and superoxides production. RNA interference with HO-1 siRNA reduced the expression of HO-1 transcripts and protein as well as oxygen radical production. Addition of the iron chelator desferrioxamine to reduce the accumulation of ferric iron from heme by HO-1 resulted in blockade of the aggravated oxygen radical production. There was no significant effect on production of oxygen radicals under these conditions in the presence of a CO donor (RuCO) or a CO scavenger (hemoglobin). In addition, the viable cells were significantly decreased in 48 h in those cells receiving simvastatin pretreatment plus LPS compared to those in control or exposed to simvastatin or LPS alone. This study revealed that simvastatin-induced HO-1 led to increased NF-B activation and superoxides production in the neuronal cells when exposed to LPS, and iron production may play a role in such a response.
Key Words: heme oxygenase-1 (HO-1); lipopolysaccharide (LPS); nuclear factor kappa B (NF-B); RNA interference (RNAi); simvastatin; zinc protoporphyrin (ZnPP).
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