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1 Departments of Internal Medicine and Molecular Pharmacology and Experimental Therapeutics, Division of Cardiovascular Diseases, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905; and 2 Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba-shi 260-8670, Japan
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+ (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
-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.
ATP-sensitive K+ channel; cardioprotection; ischemia; metabolism
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