Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics.
Although ischemic preconditioning induces bioenergetic tolerance and thereby remodels energy metabolism that is crucial for postischemic recovery of the heart, the molecular components associated with preservation of cellular energy production, transfer, and utilization are not fully understood. Here myocardial bioenergetic dynamics were assessed by (18)O-assisted (31)P-NMR spectroscopy in control or preconditioned hearts from wild-type (WT) or Kir6.2-knockout (Kir6.2-KO) mice that lack metabolism-sensing sarcolemmal ATP-sensitive K(+) (K(ATP)) channels. In WT vs. Kir6.2-KO hearts, preconditioning induced a significantly higher total ATP turnover (232 +/- 20 vs. 155 +/- 15 nmol x mg protein(-1) x min(-1)), ATP synthesis rate (58 +/- 3 vs. 46 +/- 3% (18)O labeling of gamma-ATP), and ATP consumption rate (51 +/- 4 vs. 31 +/- 4% (18)O labeling of P(i)) after ischemia-reperfusion. Moreover, preconditioning preserved cardiac creatine kinase-catalyzed phosphotransfer in WT (234 +/- 26 nmol x mg protein(-1) x min(-1)) but not Kir6.2-KO (133 +/- 18 nmol x mg protein(-1) x min(-1)) hearts. In contrast with WT hearts, preconditioning failed to preserve contractile recovery in Kir6.2-KO hearts, as tight coupling between postischemic performance and high-energy phosphoryl transfer was compromised in the K(ATP)-channel-deficient myocardium. Thus intact K(ATP) channels are integral in ischemic preconditioning-induced protection of cellular energetic dynamics and associated cardiac performance.
Gumina
Richard J
RJ
Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA.
Pucar
Darko
D
Bast
Peter
P
Hodgson
Denice M
DM
Kurtz
Christopher E
CE
Dzeja
Petras P
PP
Miki
Takashi
T
Seino
Susumu
S
Terzic
Andre
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology*; D012508:Sarcolemma / Q000378:metabolism
D024661:Potassium Channels, Inwardly Rectifying; D010725:Phosphocreatine; D000255:Adenosine Triphosphate