The Effect Of Different Time Course Of Atorvastatin Pretreatment On Myocardial Reperfusion Injury

Background:Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) possess ability to limit infarct size via the activation of the PI3K/Akt pro-survival pathway when given before ischemia-reperfusion(I/R) injury.However, previous study has demonstrated that the protective effect of atorvastatin(ATV) wanes after chronic treatment.How to recapture the lost protective effect of acute statin treatment is seldom reported.Our study aim to investigate whether intensified ATV pretreatment(loading dose of ATV before I/R) regain the lost protective effect after chronic pretreatment,and explore whether PI3K/AKT pathway is involved in this phenomenon.Methods:Sprague-Dawley rats were orally treated for one day,three days,one week,or two weeks with 20 mg/kg of atorvastatin(ATV) or vehicle,after which the hearts underwent 30 min of ischemia and 120 min reperfusion(IR).Two additional groups were treated for one or two weeks with atorvastatin and then received a supplementary dose of 40 mg/kg before IR.Plasma creatine kinase(CK),MB isoenzyme of creatine kinase(CKMB),cholesterol and triglycerides were determined using standard methods. The risk zone was determined using Evans blue and infarct size(IR%) using triphenyltetrazolium chloride(TTC) staining.Electron microscope was used to examine the ultrastructure.Results:1.Treatment with ATV for 1 and 3 days significantly reduced ischemic reperfusion injury as compared with IR control group,showing reduced plasma CK and CKMB concentrations,infarct size and Flameng score.2.After 7 or 14 days treatment,no protection was observed.The plasma CK and CKMB concentrations,infarct size and Flameng score of these two groups was not significantly different with that of IR control group.3.The loading dose of ATV before IR recaptured the lost protection after chronic treatment,and significantly reduced the plasma CK and CKMB concentrations,infarct size and Flameng score as compared with the groups treated chronically.4.AKT phosphorylation was significantly increased after ATV treatment for 1 and 3 days. However,treatment with ATV for 7 and 14 days increased the level of PTEN,and reduced AKT phosphorylation.5.The loading dose of ATV reactivated AKT,although it did not change the level of PTEN.6.Treatment with ATV for 1 and 3 days did not lower the plasma triglycerides(P>0.05),whereas treatment with ATV for 7 and 14 significantly lowered the plasma triglycerides(P<0.05).The loading dose of ATV did not further change the plasma triglycerides(P>0.05).ATV did not lower plasma cholesterol concentrations regardless the time of ATV treatment.Conclusion:Treatment with ATV for 1 and 3 days significantly reduced ischemic reperfusion injury,whereas this protective effect wanes after 7 and 14 days treatment.The acute ATV pretreatment might activate AKT,thus protecting the myocardium against reperfusion injury;however,chronic pretreatment of ATV might increase the level of PTEN which inactivated AKT,thus losing the ability to reduce infarct size.The loading dose of ATV reactivating AKT and recapturing the beneficial effect does not further change lipids,which demonstrate that the loss of protective effect is not relevant to the excessive reduction of lipids.