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  • Title: Rosiglitazone-induced myocardial protection against ischaemia-reperfusion injury is mediated via a phosphatidylinositol 3-kinase/Akt-dependent pathway.
    Author: Zhang XJ, Xiong ZB, Tang AL, Ma H, Ma YD, Wu JG, Dong YG.
    Journal: Clin Exp Pharmacol Physiol; 2010 Feb; 37(2):156-61. PubMed ID: 19566839.
    Abstract:
    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.
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