Statin-induced heme oxygenase-1 increases NF-kappaB activation and oxygen radical production in cultured neuronal cells exposed to lipopolysaccharide.
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-kappaB) activation, manifested as IkappaBalpha 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-kappaB 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-kappaB activation and superoxides production in the neuronal cells when exposed to LPS, and iron production may play a role in such a response.
Hsieh
Ching-Hua
CH
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Hsien, Taiwan.
Jeng
Seng-Feng
SF
Hsieh
Min-Wei
MW
Chen
Yi-Chun
YC
Rau
Cheng-Shyuan
CS
Lu
Tsu-Hsiang
TH
Chen
Shun-Sheng
SS
D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D020672:I-kappa B Proteins; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009249:NADP / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011524:Protoporphyrins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019821:Simvastatin / Q000633:toxicity*; D051996:Transcription Factor RelA / Q000378:metabolism
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020672:I-kappa B Proteins; D007502:Iron Chelating Agents; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D011524:Protoporphyrins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; C017803:zinc protoporphyrin; D009249:NADP; D019821:Simvastatin; D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C491523:Hmox1 protein, rat; D003676:Deferoxamine