Statin-induced heme oxygenase-1 increases NF-κB activation and oxygen radical production in cultured neuronal cells exposed to lipopolysaccharide

Ching Hua Hsieh, Seng Feng Jeng, Min Wei Hsieh, Yi Chun Chen, Cheng Shyuan Rau, Tsu Hsiang Lu, Shun Sheng Chen*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

28 Scopus citations


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-κB) activation, manifested as IκBα 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-κB 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-κB activation and superoxides production in the neuronal cells when exposed to LPS, and iron production may play a role in such a response.

Original languageEnglish
Pages (from-to)150-159
Number of pages10
JournalToxicological Sciences
Issue number1
StatePublished - 03 2008


  • Heme oxygenase-1 (HO-1)
  • Lipopolysaccharide (LPS)
  • Nuclear factor kappa B (NF-κB)
  • RNA interference (RNAi)
  • Simvastatin
  • Zinc protoporphyrin (ZnPP)


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