title: Simvastatin inhibits pro-inflammatory mediators through induction of heme oxygenase-1 expression in lipopolysaccharide-stimulated RAW264.7 macrophages.
abstract: It has been reported that the anti-inflammatory activity of 3-hydroxy-3-methyl-glutary coenzyme A (HMG-CoA) reductase inhibitors (statins) is independent of their hypocholesterolemic effect. Previous studies indicated that induction of heme oxygenase-1 (HO-1) exerts a cytoprotective activity in several inflammatory diseases. Here, the possibility that HO-1 is involved in the anti-inflammatory action of simvastatin, using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages as a model system has been specifically addressed. Our results demonstrated that in the presence of LPS, simvastatin significantly increased HO-1 expression and activity in a dose-dependent manner compared to that of LPS-stimulated alone macrophages. Moreover, simvastatin significantly inhibited LPS-induced inducible nitric oxide synthase (NOS) expression, and formation of pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), nitrite and free radicals, but enhanced interleukin-10 (IL-10) production. Similarly, the IκB-α degradation and nuclear transcription factor-κB translocation and activation caused by LPS were significantly suppressed by simvastatin. However, these anti-inflammatory activities of simvastatin were markedly reversed by addition of a HO-1 inhibitor zinc protoporphyrin (ZnPP). Accordingly, the present results indicate that the anti-inflammatory activity of simvastatin could, at least in part, be regulated by induction of HO-1-mediated processes.
authors.affiliation: Department of Intensive Care, Chi Mei Medical Center, Liouying, Tainan, Taiwan.
authors.forename: Pak-On
authors.initials: PO
authors.lastname: Leung
authors.forename: Sue-Hong
authors.initials: SH
authors.lastname: Wang
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Lu
authors.forename: Wen-Hsiang
authors.initials: WH
authors.lastname: Chou
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Shiau
authors.forename: Tz-Chong
authors.initials: TC
authors.lastname: Chou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005609:Free Radicals / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D005609:Free Radicals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1