Background During ischaemia, AMPK activation occurs in order to provide energy from alternative resources. However, AMPK activity is known to be impaired in diabetes. We hypothesised that enhancing AMPK activation above physiological levels during ischaemia would protect both the normoglycaemic and the diabetic heart.
Methodology Hearts from Wistar and Goto Kakizaki rats (GK, a mildly diabetic rat strain) were subjected to 35 min coronary artery occlusion in the presence of 10, 20 or 40 μM A-769662 (an activator of AMPK), followed by 120 min of reperfusion with normal buffer (n ≥ 6). Risk zone and myocardial infarction were assessed using Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, respectively and expressed as percentage of the area at risk (I/R%). The effect of A-769662 on mitochondrial permeability transition (opening of the mPT pore is associated with reperfusion injury) was also investigated by exposing rat cardiomyocytes loaded with the fluorophore TMRM to a laser oxidative insult; the time to mitochondrial membrane depolarisation and rigour contracture were measured (n=6, 80–100 cells/assay).
Results A-769662 reduced the infarct size in both the normoglycaemic and diabetic hearts in comparison with control hearts at 20 μM (31.8%±3.1 vs 51.4%±1.5 normoglycaemic heart; 22.7%±3.0 vs 37.6%±2.7 for the GK heart; p<0.05) and at 40 μM (35.6%±1.9 vs 51.4%±1.5 for the normoglycaemic heart; 18.6%±1.6 vs 37.6%±2.7, for the GK heart; p<0.05) In addition, A-769662 also significantly delayed the mPTP opening (147.71%±10.2% at 20 μM, 146.7%±15.6% at 40 μM, vs control 100%, p<0.05).
Conclusions Our data suggest that the enhancement of AMPK activity during ischaemia may lead to infarct reduction and delayed opening of the mPTP in the ischaemic reperfused rat heart.
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