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Transitory Activation of AMPK at Reperfusion Protects the Ischaemic-Reperfused Rat Myocardium Against Infarction

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Abstract

Purpose

AMPK plays a crucial role in the regulation of the energy metabolism of the heart. During ischaemia, AMPK activation is a known adaptative prosurvival mechanism that helps to maintain the energy levels of the myocardium. However, it still remains unclear if activation of AMPK during reperfusion is beneficial for the heart. Two known AMPK activators (metformin and AICAR) were used to verify the hypothesis that a transitory activation of AMPK at reperfusion may exert cardioprotection, as reflected in a reduction in myocardial infarct size.

Methods

Perfused rat hearts were subjected to 35 min ischaemia and 120 min reperfusion. Metformin (50 μM) or AICAR (0.5 mM) were added for 15 min at the onset of reperfusion alone or with Compound C (CC, 10 μM), an AMPK inhibitor. Infarct size and α-AMPK phosphorylation were measured.

Results

Metformin significantly reduced infarct size from 47.8 ± 1.7% in control to 31.4 ± 2.9%, an effect abolished by CC when the drugs were given concomitantly. Similarly, AICAR also induced a significant reduction in infarct size to 32.3 ± 4.8%, an effect also abrogated by CC. However, metformin’s protection was not abolished if CC was administered later in reperfusion. In addition, α-AMPK phosphorylation was significantly increased in the metformin treated group during the initial 30 min of reperfusion.

Conclusions

Our data demonstrated that, in our ex vivo model of myocardial ischaemia-reperfusion injury, AMPK activation in early reperfusion is associated with a reduction in infarct size.

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Acknowledgments

MA Paiva is a recipient of a fellowship by Fundação para a Ciência e Tecnologia (SFRH/BD/23671/2005). We thank British Heart Foundation for continuous support.

Conflict of interest

The authors state no conflict of interest.

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Authors and Affiliations

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

    Marta A. Paiva, Sean M. Davidson, Derek M. Yellon & Mihaela M. Mocanu

  2. Basic Research in Cardiology Unit, IBILI, Coimbra University Hospital and Coimbra Medical School, Coimbra, Portugal

    Marta A. Paiva, Lino M. Gonçalves & Luis A. Providência

Authors
  1. Marta A. Paiva
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  2. Lino M. Gonçalves
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  3. Luis A. Providência
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  4. Sean M. Davidson
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  5. Derek M. Yellon
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  6. Mihaela M. Mocanu
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Correspondence to Derek M. Yellon.

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Paiva, M.A., Gonçalves, L.M., Providência, L.A. et al. Transitory Activation of AMPK at Reperfusion Protects the Ischaemic-Reperfused Rat Myocardium Against Infarction. Cardiovasc Drugs Ther 24, 25–32 (2010). https://doi.org/10.1007/s10557-010-6222-3

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