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.
Lai
I-Rue
IR
Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. 2
Chang
King-Jen
KJ
Tsai
Hsiu-Wen
HW
Chen
Chau-Fong
CF
D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods; D008099:Liver / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D019821:Simvastatin / Q000627:therapeutic use*
D019821:Simvastatin; D051547:Heme Oxygenase-1; D000410:Alanine Transaminase