Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction.
OBJECTIVE
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 microM) or AICAR (0.5 mM) were added for 15 min at the onset of reperfusion alone or with Compound C (CC, 10 microM), an AMPK inhibitor. Infarct size and alpha-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, alpha-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.
Paiva
Marta A
MA
The Hatter Cardiovascular Institute, University College London Hospitals and Medical School, UK.
Gonçalves
Lino M
LM
Providência
Luis A
LA
Davidson
Sean M
SM
Yellon
Derek M
DM
Mocanu
Mihaela M
MM
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007238:Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D007004:Hypoglycemic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide