Fluvastatin inhibits the induction of inducible nitric oxide synthase, an inflammatory biomarker, in hepatocytes.

ABSTRACT

AIM: Statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors), which were originally designed to lower plasma cholesterol levels, are increasingly recognized as anti-inflammatory agents. In the inflamed liver, pro-inflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS). Overproduction of NO by iNOS has been implicated as a factor in liver injury. We examined pro-inflammatory cytokine-stimulated hepatocytes as a simple in vitro injury model to determine liver-protective effects of statins. We hypothesized that statins are involved in the downregulation of iNOS, resulting in decreased hepatic inflammation. METHODS: Hepatocytes were isolated from rats by collagenase perfusion and centrifugation. Primary cultured hepatocytes were treated with interleukin (IL)-1ß in the presence or absence of fluvastatin. The induction of iNOS and its signaling pathway were analyzed. RESULTS: IL-1ß produced increased levels of NO. This effect was inhibited by fluvastatin, which exerted its maximal effects at 100 µM. Fluvastatin decreased the levels of iNOS protein and its mRNA expression. Fluvastatin had no effects on IκB degradation and nuclear factor-κB activation. However, fluvastatin inhibited the upregulation of type I IL-1 receptor mRNA and protein expression. Transfection experiments demonstrated that fluvastatin suppressed iNOS induction by the inhibition of promoter transactivation and mRNA stabilization. Fluvastatin reduced the expression of an iNOS gene antisense-transcript, which is involved in iNOS mRNA stability. CONCLUSION: Results indicate that fluvastatin inhibits the induction of iNOS at both transcriptional and post-transcriptional steps, leading to the prevention of NO production. Fluvastatin may provide therapeutic potential in iNOS induction involved in various liver injuries.