title: Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury.
abstract: AMPK activation during ischemia helps the myocardium to cope with the deficit of energy production. As AMPK activity is considered to be impaired in diabetes, we hypothesized that enhancing AMPK activation during ischemia above physiological levels would protect the ischemic diabetic heart through AMPK activation and subsequent inhibition of mitochondrial permeability transition pore (mPTP) opening. Isolated perfused hearts from normoglycemic Wistar or diabetic Goto-Kakizaki (GK) rats (n ≥ 6/group) were subjected to 35 min of ischemia in the presence of 10, 20, and 40 μM of A-769662, a known activator of AMPK, followed by 120 min of reperfusion with normal buffer. Myocardial infarction and AMPK phosphorylation were assessed. The effect of A-769662 on mPTP opening in adult cardiomyocytes isolated from both strains was also determined. A-769662 at 20 μM reduced infarct size in both Wistar (30.5 ± 2.7 vs. 51.8 ± 3.9% vehicle; P < 0.001) and GK hearts (22.7 ± 3.0 vs. 48.5 ± 4.7% vehicle; P < 0.001). This protection was accompanied by a significant increase in AMPK and GSK-3β phosphorylation. In addition, A-769662 significantly inhibited mPTP opening in both Wistar and GK cardiomyocytes subjected to oxidative stress. We demonstrate that AMPK activation during ischemia via A-769662 reduces myocardial infarct size in both the nondiabetic and diabetic rat heart. Furthermore, this cardioprotective effect appears to be mediated through inhibition of mPTP opening. Our findings suggest that improving AMPK activation during ischemia can be another mechanism for protecting the ischemic heart.
authors.affiliation: Hatter Cardiovascular Institute, Univ. College London Hospitals, 67 Chenies Mews, London, WC1E 6HX, UK.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Paiva
authors.forename: Zoe
authors.initials: Z
authors.lastname: Rutter-Locher
authors.forename: Lino M
authors.initials: LM
authors.lastname: Gonçalves
authors.forename: Luís A
authors.initials: LA
authors.lastname: Providência
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
authors.forename: Mihaela M
authors.initials: MM
authors.lastname: Mocanu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011753:Pyrones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D055372:AMP-Activated Protein Kinases; D001713:Biphenyl Compounds; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011753:Pyrones; D013876:Thiophenes; C526109:Anxa3 protein, rat; C000605508:Gsk3b protein, rat; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile