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rIPC [remote IPC (ischaemic preconditioning)] has been shown to invoke potent myocardial protection in animal studies and recent clinical trials. Although the important role of PI3K (phosphoinositide 3-kinase)/Akt activation in the cardioprotection afforded by local IPC is well described, our understanding of the intracellular signalling of rIPC remains incomplete. We therefore examined the hypothesis that the myocardial protection afforded by rIPC is mediated via the PI3K/Akt/GSK3β (glycogen synthase kinase 3β) signalling pathway, activation of which is associated with nuclear accumulation of β-catenin. rIPC was induced in mice using four cycles of 5 min of ischaemia and 5 min of reperfusion of the hindlimb using a torniquet. This led to reduced infarct size (19 ± 4% in rIPC compared with 39 ± 7% in sham; P<0.05), improved functional recovery and reduced apoptosis after global I/R (ischaemia/reperfusion) injury using a Langendorff-perfused mouse heart model. These effects were reversed by pre-treatment with an inhibitor of PI3K activity. Furthermore, Western blot analysis demonstrated that, compared with control, rIPC was associated with activation of the PI3K/Akt signalling pathway, resulting in phosphorylation and inactivation of GSK3β, accumulation of β-catenin in the cytosol and its translocation to the nucleus. Finally, rIPC increased the expression of β-catenin target genes involved in cell-survival signalling, including E-cadherin and PPARδ (peroxisome-proliferator-activated receptor δ). In conclusion, we show for the first time that the myocardial protection afforded by rIPC is mediated via the PI3K/Akt/GSK3β signalling pathway, activation of which is associated with nuclear accumulation of β-catenin and the up-regulation of its downstream targets E-cadherin and PPARδ involved in cell survival.

Original publication

DOI

10.1042/CS20100466

Type

Journal article

Journal

Clin Sci (Lond)

Publication Date

05/2011

Volume

120

Pages

451 - 462

Keywords

Animals, Apoptosis, Cadherins, Cell Nucleus, Disease Models, Animal, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Ischemic Preconditioning, Myocardial, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, PPAR delta, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction, Up-Regulation, beta Catenin