Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics
Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics
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DOI：
10.1152/ajpheart.00057.2003
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发表时间：
2003-06-01
影响因子：
4.8
通讯作者：
Terzic, A
中科院分区：
文献类型：
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作者：
Gumina, RJ;Pucar, D;Terzic, A
虽然缺血预处理诱导生物能耐受，从而重塑能量代谢，这是至关重要的缺血后恢复的心脏，与细胞能量的生产，转移和利用的保存相关的分子组成部分还没有完全理解。在此，通过O-18-辅助P-31-NMR光谱法在来自野生型（WT）或Kir6.2-敲除（Kir6.2-KO）小鼠的对照或预处理心脏中评估心肌生物能量动力学，所述小鼠缺乏代谢敏感肌膜ATP敏感性K+（K-ATP）通道。在WT与Kir6.2-KO心脏中，缺血再灌注后，预处理诱导了显著更高的总ATP周转率（232 +/- 20 vs. 155 +/- 15 nmol.mg protein（-1）.min（-1））、ATP合成率（58 +/- 3 vs. 46 +/-3%O-18标记的γ-ATP）和ATP消耗率（51 +/- 4 vs. 31 +/-4%O-18标记的Pi）。此外，预处理可保护WT（234 +/- 26 nmol.mg protein（-1）.min（-1））心脏中心肌肌酸激酶催化的磷酸转移，但不能保护Kir6.2-KO（133 +/- 18 nmol.mg protein（-1）.min（-1））心脏。与WT心脏相比，预处理未能保持Kir6.2-KO心脏的收缩恢复，因为在K-ATP通道缺陷的心肌中，缺血后性能和高能磷酰基转移之间的紧密耦合受到损害。因此，完整的K-ATP通道在缺血预处理诱导的细胞能量动力学和相关心脏性能的保护中不可或缺。
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 O-18-assisted P-31-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% O-18 labeling of gamma-ATP), and ATP consumption rate (51 +/- 4 vs. 31 +/- 4% O-18 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 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.