Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction

MA Paiva, LM Gonçalves, LA Providência… - … drugs and therapy, 2010 - Springer
MA Paiva, LM Gonçalves, LA Providência, SM Davidson, DM Yellon, MM Mocanu
Cardiovascular drugs and therapy, 2010Springer
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 …
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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