Simvastatin inhibits pro-inflammatory mediators through induction of heme oxygenase-1 expression in lipopolysaccharide-stimulated RAW264.7 macrophages

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.

► The role of HO-1 in the anti-inflammatory action of simvastatin was examined. ► Simvastatin reduced LPS-induced iNOS expression, and TNF-α formation in macrophages. ► The LPS-induced NF-κB activation was also inhibited by simvastatin. ► However, the actions of simvastatin were markedly reversed by a HO-1 inhibitor. ► The anti-inflammatory activity of simvastatin may be regulated by HO-1.