Pharmacological preconditioning with simvastatin protects liver from ischemia-reperfusion injury by heme oxygenase-1 induction

Background. The protective role of heme oxygenase-1 (HO-1) against liver ischemia-reperfusion (I/R) injury in models of hypoxic and remote preconditioning has been proved. The feasible candidates who induce HO-1 and thorough which exert the protective effects are under investigation. The aim was to study the role of HO-1 in pharmacological preconditioning by simvastatin in a rat model. Methods. Pharmacological preconditioning by intraperitoneal injection of simvastatin (5 mg/kg) was tested on a partial liver I/R model on rats. The expression of HO-1 protein and enzyme activities in livers, serum alanine transaminase (ALT) levels, and TUNEL staining of liver after I/R injury were measured in rats with and without simvastatin preconditioning. Results. HO-1 was induced and persistently overexpressed in the hepatocytes 24 hr after simvastatin treatment. Simvastatin preconditioning diminished the elevation of serum ALT levels 4 hr after I/R injury (69.6 +/- 26.3 U/L) (P<0.05 vs. other groups) when compared with control (403.8 +/- 261.9 U/L) and zinc protoporphyrin (ZnPP)-pretreated (717.5 +/- 205.6 U/L) groups. Simvastatin preconditioning diminished the apoptosis after I/R injury as well (apoptosis index: 26.4 +/- 8 for Simvastatin, 78 +/- 7 for control, and 85.3 +/- 2 for ZnPP group; P<0.05). The addition of ZnPP negated the protective effects of simvastatin as evidenced in the ALT level (406.2 +/- 243.0 U/L) and apoptosis index (75.6 +/- 6). The heme oxygenase activity in treated rats correlated with these results. Conclusions. The induction of HO-1 by simvastatin preconditioning played a protective role against hepatic I/R injury.