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.
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May 2011
Research Article|
January 28 2011
Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of β-catenin
Jing Li;
Jing Li
*Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8
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Wanli Xuan;
Wanli Xuan
*Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8
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Ran Yan;
Ran Yan
†Health Sciences Program, McMaster University, Hamilton, Ontario, Canada L8S4L8
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Michael B. Tropak;
Michael B. Tropak
‡Genetic & Metabolic Laboratory Medicine, Hospital for Sick Children, Toronto, Canada M5G1X8
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Emilie Jean-St-Michel;
Emilie Jean-St-Michel
*Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8
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Wenbin Liang;
Wenbin Liang
§Departments of Physiology and Medicine, University of Toronto, Toronto, Canada
∥Division of Cardiology, University Health Network, Toronto, Ontario, Canada M5G1X8
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Rachel Gladstone;
Rachel Gladstone
*Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8
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Peter H. Backx;
Peter H. Backx
§Departments of Physiology and Medicine, University of Toronto, Toronto, Canada
∥Division of Cardiology, University Health Network, Toronto, Ontario, Canada M5G1X8
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Rajesh K. Kharbanda;
Rajesh K. Kharbanda
¶Department of Cardiovascular Medicine, The John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, U.K.
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Andrew N. Redington
*Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8
Correspondence: Professor Andrew N. Redington (email andrew.redington@sickkids.ca).
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Clin Sci (Lond) (2011) 120 (10): 451–462.
Article history
Received:
September 17 2010
Revision Received:
November 17 2010
Accepted:
December 08 2010
Accepted Manuscript online:
December 08 2010
Citation
Jing Li, Wanli Xuan, Ran Yan, Michael B. Tropak, Emilie Jean-St-Michel, Wenbin Liang, Rachel Gladstone, Peter H. Backx, Rajesh K. Kharbanda, Andrew N. Redington; Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of β-catenin. Clin Sci (Lond) 1 May 2011; 120 (10): 451–462. doi: https://doi.org/10.1042/CS20100466
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