ToxSci Advance Access published online on October 10, 2007
Toxicological Sciences, 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
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan * Department of Neurosurgery, Chang Gung Memorial Hospital – Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan ** Department of Plastic Surgery, Chang Gung Memorial Hospital – Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan *** Department of Neurology, Chang Gung Memorial Hospital – Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan
ADDRESS REPRINT REQUESTS TO: Shun-Sheng Chen, M.D., PhD., Department of Neurology, Chang Gung Memorial Hospital – Kaohsiung Medical Center, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien, Taiwan, Tel: 886-7-7317123-8325 Fax: 886-7-07-7328828, e-mail: m93chinghua{at}gmail.com
Received August 10, 2007; revision received October 1, 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. However, overexpression of HO-1 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 Nrf2, which was expressed by Western blots of nuclear fractions and retarded complex formation in the EMSA reaction. In addition, simvastatin activated the ERK and p38, but not the phosphorylation of JNK and Akt. Glucose deprivation in the cells pretreated with simvastatin induced more HO-1 expression, and the transcript could be decreased by siRNA 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); NF-E2-related factor 2 (Nrf2); Simvastatin; Zinc protoprophyrin (ZnPP).
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