title: Dual cardiac contractile effects of the alpha2-AMPK deletion in low-flow ischemia and reperfusion.
abstract: Because the question "is AMP-activated protein kinase (AMPK) alpha(2)-isoform a friend or a foe in the protection of the myocardium against ischemia-reperfusion injury?" is still in debate, we studied the functional consequence of its deletion on the contractility, the energetics, and the respiration of the isolated perfused heart and characterized the response to low-flow ischemia and reperfusion with glucose and pyruvate as substrates. alpha(2)-AMPK deletion did not affect basal contractility, respiration, and high-energy phosphate contents but induced a twofold reduction in glycogen content and a threefold reduction in glucose uptake. Low-flow ischemia increased AMPK phosphorylation and stimulated glucose uptake and phosphorylation in both alpha(2)-knockout (alpha(2)-KO) and wild-type (WT) groups. The high sensitivity of alpha(2)-KO to the development of ischemic contracture was attributed to the constitutive impairment in glucose transport and glycogen content and not to a perturbation of the energy transfer by creatine kinase (CK). The functional coupling of MM-CK to myofibrillar ATPase and the CK fluxes were indeed similar in alpha(2)-KO and WT. Low-flow ischemia impaired CK flux by 50% in both strains, showing that alpha(2)-AMPK does not control CK activity. Despite the higher sensitivity to contracture, the postischemic contractility recovered to similar levels in both alpha(2)-KO and WT in the absence of fatty acids. In their presence, alpha(2)-AMPK deletion also accelerated the contracture but delayed postischemic contractile recovery. In conclusion, alpha(2)-AMPK is required for a normal glucose uptake and glycogen content, which protects the heart from the development of the ischemic contracture, but not for contractile recovery in the absence of fatty acids.
authors.affiliation: INSERM U-769, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Karla
authors.initials: K
authors.lastname: Carvajal
authors.forename: Elham
authors.initials: E
authors.lastname: Zarrinpashneh
authors.forename: Ondrej
authors.initials: O
authors.lastname: Szarszoi
authors.forename: Frederic
authors.initials: F
authors.lastname: Joubert
authors.forename: Yoni
authors.initials: Y
authors.lastname: Athea
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gillet
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Xavier
authors.initials: X
authors.lastname: Bigard
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Hoerter
mesh_terms: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration; D052283:Creatine Kinase, MM Form / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010101:Oxygen Consumption; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D009097:Multienzyme Complexes; D010725:Phosphocreatine; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D052283:Creatine Kinase, MM Form; D005947:Glucose