1.
Rosiglitazone is widely used in the treatment of
Type 2 diabetes. However, in recent years it has become evident that the
therapeutic effects of
peroxisome proliferator-activated receptor gamma ligands reach far beyond their use as
insulin sensitizers. Recently, the ability of
rosiglitazone pretreatment to induce cardioprotection following ischaemia-reperfusion (I/R) has been well documented; however, the protective mechanisms have not been elucidated. In the present study, examined the role of the
phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway in
rosiglitazone cardioprotection following I/R injury. 2. Mice were pretreated with 3 mg/kg per day
rosiglitazone for 14 days before hearts were subjected to ischaemia (30 min) and reperfusion (2 h).
Wortmannin (1.4 mg/kg, i.p.), an inhibitor of PI3-K, was administered 10 min prior to myocardial I/R. Then, activation of the PI3-K/Akt/
glycogen synthase kinase (GSK)-3alpha signalling pathway was examined. The effects of PI3-K inhibition on
rosiglitazone-induced cardioprotection were also evaluated. 3. Compared with control rats, the ratio of
infarct size to ischaemic area (area at risk) and the occurrence of sustained
ventricular fibrillation in
rosiglitazone-pretreated rats was significantly reduced (P < 0.05).
Rosiglitazone pretreatment attenuated cardiac apoptosis, as assessed by ELISA to determine cardiomyocyte DNA fragmentation.
Rosiglitazone pretreatment significantly increased levels of phosphorylated (p-) Akt and p-GSK-3alpha in the rat myocardium. Pharmacological inhibition of PI3-K by
wortmannin markedly abolished the cardioprotection induced by
rosiglitazone. 4. These results indicate that
rosiglitazone-induced cardioprotection in I/R injury is mediated via a PI3-K/Akt/GSK-3alpha-dependent pathway. The data also suggest that modulation of PI3-K/Akt/GSK-3alpha-dependent signalling pathways may be a viable strategy to reduce myocardial I/R injury.