Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts.
Activation of 5'-AMP-activated protein kinase (AMPK) may benefit the heart during ischemia-reperfusion by increasing energy production. While AMPK stimulates glycolysis, mitochondrial oxidative metabolism is the major source of ATP production during reperfusion of ischemic hearts. Stimulating AMPK increases mitochondrial fatty acid oxidation, but this is usually accompanied by a decrease in glucose oxidation, which can impair the functional recovery of ischemic hearts. To examine the relationship between AMPK and cardiac energy substrate metabolism, we subjected isolated working mouse hearts expressing a dominant negative (DN) alpha(2)-subunit of AMPK (AMPK-alpha(2) DN) to 20 min of global no-flow ischemia and 40 min of reperfusion with Krebs-Henseleit solution containing 5 mM [U-(14)C]glucose, 0.4 mM [9, 10-(3)H]palmitate, and 100 microU/ml insulin. AMPK-alpha(2) DN hearts had reduced AMPK activity at the end of reperfusion (82 +/- 9 vs. 141 +/- 7 pmol.mg(-1).min(-1)) with no changes in high-energy phosphates. Despite this, AMPK-alpha(2) DN hearts had improved recovery of function during reperfusion (14.9 +/- 0.8 vs. 9.4 +/- 1.4 beats.min(-1).mmHg.10(-3)). During reperfusion, fatty acid oxidation provided 44.0 +/- 2.8% of total acetyl-CoA in AMPK-alpha(2) DN hearts compared with 55.0 +/- 3.2% in control hearts. Since insulin can inhibit both AMPK activation and fatty acid oxidation, we also examined functional recovery in the absence of insulin. Functional recovery was similar in both groups despite a decrease in AMPK activity and a decreased reliance on fatty acid oxidation during reperfusion (66.4 +/- 9.4% vs. 85.3 +/- 4.3%). These data demonstrate that the suppression of cardiac AMPK activity does not produce an energetically compromised phenotype and does not impair, but may in fact improve, the recovery of function after ischemia.
Cardiovascular Research Group and Department of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Clifford D L
CD
Folmes
Cory S
CS
Wagg
Mei
M
Shen
Alexander S
AS
Clanachan
Rong
R
Tian
Gary D
GD
Lopaschuk
D055372:AMP-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D010168:Palmitates / Q000378:metabolism; D020127:Recovery of Function
D000227:Adenine Nucleotides; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D010168:Palmitates; D000105:Acetyl Coenzyme A; D006003:Glycogen; C534978:Prkaa2 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases