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Investigating the Signal Transduction Pathways Underlying Remote Ischemic Conditioning in the Porcine Heart

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Abstract

Background

The mechanism underlying remote ischemic conditioning (RIC) remains unclear. We investigated whether RIC protects the heart through the activation of the adenosine receptor and the PI3K-Akt pathway at the onset of myocardial reperfusion.

Methods and results

Domestic pigs (27–35 kg) were subjected to in situ left anterior descending coronary artery ischemia (60 min) followed by reperfusion (180 min) and randomised to the following: (1) Control- No additional intervention; (2) Remote ischemic preconditioning (RIPC)- Four-5 min cycles of lower limb ischemia/reperfusion were administered prior to myocardial ischemia; (3) RIPC + Wort or 8-SPT: Wortmannin (Wort 20 μg/kg, a PI3K inhibitor) or 8-sulfophenyltheophylline (8-SPT 10 mg/kg, an adenosine receptor inhibitor) were administered intravenously 30 s before myocardial reperfusion to RIPC-treated animals; (4) Remote ischemic perconditioning (RIPerC)- Four-5 min cycles of lower limb ischemia/reperfusion were applied 1 min before myocardial reperfusion; (5) RIPerC + Wort or 8-SPT: Wort or 8-SPT were given 30 s before myocardial reperfusion to RIPerC-treated animals. Both RIPC and RIPerC reduced myocardial infarct size (13.3 ± 2.2% with RIPC, 18.2 ± 2.0% with RIPerC versus 48.8 ± 4.2% in control:P < 0.05:N ≥ 5/group). Wortmannin abolished the infarct-limiting effects of RIPC (33.2 ± 6% with RIPC + Wort versus 13.3 ± 2.2% with RIPC:P < 0.05:N ≥ 5/group) but not RIPerC (18.0 ± 3.4% with RIPerC + Wort versus 18.2 ± 2.0% with RIPerC:P > 0.05:N ≥ 5/group). 8-SPT did not influence the infarct-limiting effects of either RIPC or RIPerC. Western blot analysis confirmed Wortmannin-sensitive PI3K and Akt activation at myocardial reperfusion in RIPC-treated hearts.

Conclusions

In the porcine heart, both RIPC and RIPerC both reduce myocardial infarct size and with RIPC but not RIPerC this cardioprotective effect is associated with the activation of the PI3K-Akt pathway at reperfusion.

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Acknowledgements

We thank ELPEN Pharmaceutical Co. Inc. for continued support.

Funding

We wish to thank the British Heart Foundation for continued support.

Conflict of interest

None declared.

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Authors and Affiliations

  1. The Hatter Cardiovascular Institute, University College London Hospital & Medical School, London, UK

    D. J. Hausenloy & D. M. Yellon

  2. 2nd University Department of Cardiology, Attikon General Hospital, Medical School, University of Athens, Athens, Greece

    E. K. Iliodromitis, A. Papalois, G. Gritsopoulos, M. Anastasiou-Nana & D. T. Kremastinos

  3. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Athens, Greece

    I. Andreadou

  4. The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX, UK

    D. M. Yellon

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  1. D. J. Hausenloy
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  2. E. K. Iliodromitis
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Correspondence to D. M. Yellon.

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Hausenloy, D.J., Iliodromitis, E.K., Andreadou, I. et al. Investigating the Signal Transduction Pathways Underlying Remote Ischemic Conditioning in the Porcine Heart. Cardiovasc Drugs Ther 26, 87–93 (2012). https://doi.org/10.1007/s10557-011-6364-y

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  • DOI: https://doi.org/10.1007/s10557-011-6364-y

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