Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics

Abstract

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 by18O-assisted 31P-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+ (KATP) channels. In WT vs. Kir6.2-KO hearts, preconditioning induced a significantly higher total ATP turnover (232 ± 20 vs. 155 ± 15 nmol · mg protein−1 · min−1), ATP synthesis rate (58 ± 3 vs. 46 ± 3% 18O labeling of γ-ATP), and ATP consumption rate (51 ± 4 vs. 31 ± 4% 18O labeling of Pi) after ischemia-reperfusion. Moreover, preconditioning preserved cardiac creatine kinase-catalyzed phosphotransfer in WT (234 ± 26 nmol · mg protein−1 · min−1) but not Kir6.2-KO (133 ± 18 nmol · mg protein−1 · 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 KATP-channel-deficient myocardium. Thus intact KATP channels are integral in ischemic preconditioning-induced protection of cellular energetic dynamics and associated cardiac performance.