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 ¹⁸O-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⁺ (K_ATP) 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 P_i) 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 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.