ToxSci Advance Access originally published online on October 10, 2007
Toxicological Sciences 2008 101(1):112-121; doi:10.1093/toxsci/kfm258
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Simvastatin-Induced Heme Oxygenase-1 Increases Apoptosis of Neuro 2A Cells in Response to Glucose Deprivation
,1
* Graduate Institute of Clinical Medical Sciences
Department of Neurosurgery
Department of Plastic Surgery
Department of Neurology, Chang Gung Memorial Hospital—Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan 833
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 August 10, 2007; accepted October 1, 2007
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Abstract |
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Heme oxygenase-1 (HO-1) has been suggested as an important mediator of the cholesterol-independent cytoprotection actions of statins, which may be of benefit for the treatment of degenerative neurological diseases and for reduction of infarct volume after cerebral ischemia. Overexpression of HO-1, however, has dual effects under oxidative stress, and the release of ferric iron from heme under these conditions may result in detrimental rather than cytoprotective effects. This study was designed to investigate the effect of simvastatin-induced HO-1 on Neuro 2A cells in response to glucose deprivation. We demonstrated that simvastatin induced a dose- and time-dependent upregulation of HO-1 protein expression in Neuro 2A cells. The induction of HO-1 after simvastatin treatment was mediated by nuclear factor erythroid 2–related factor 2 (Nrf2), which was expressed by Western blots of nuclear fractions and retarded complex formation in the electrophoretic mobility shift assay reaction. In addition, simvastatin activated the extracellular signal–regulated kinase and p38, but not the phosphorylation of c-Jun N-terminal kinase and Akt. Glucose deprivation in the cells pretreated with simvastatin induced more HO-1 expression, and the transcript could be decreased by small interfering RNA for Nrf2. This upregulation of HO-1 was significantly associated with increased apoptosis, manifested as expression at the protein level of 17-kDa cleaved caspase-3 and increased percentage of apoptotic cells shown by flow cytometry. The increased cleaved caspase-3 expression and percentage of apoptotic cells was significantly reduced by the HO inhibitor zinc protoporphyrin. Addition of the iron chelator desferrioxamine also resulted in blockade of the aggravated apoptosis, which implies that iron production from HO-1 activity may play an important role in the increased apoptosis in response to glucose deprivation in neuronal cells pretreated with simvastatin.
Key Words: apoptosis; desferrioxamine (DFO); glucose deprivation; heme oxygenase-1 (HO-1); nuclear factor erythroid 2–related factor 2–related factor 2 (Nrf2); simvastatin; zinc protoprophyrin (ZnPP).
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