Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways.
Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways.
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DOI：
10.1016/j.yjmcc.2012.03.016
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发表时间：
2012-07
影响因子：
5
通讯作者：
William G. Witham;Keith A. Yester;C. O'Donnell;Kenneth R. Mcgaffin
中科院分区：
文献类型：
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作者：
William G. Witham;Keith A. Yester;C. O'Donnell;Kenneth R. Mcgaffin
在正常心脏中，瘦素调节心脏代谢。然而，瘦素对急性心肌梗死（MI）患者心脏代谢和预后的影响尚不清楚。这项研究是为了验证瘦素信号增加葡萄糖代谢和减轻急性梗死心脏损伤的假设。将具有（ObR+/+）和不具有（ObR−/−）心肌细胞特异性表达瘦素受体（ObR）的小鼠随机分配到实验性MI或假手术组，并在3d后进行研究。ObR+/+和ObR−/−假手术小鼠在任何测量结果上均无显著差异。然而，在MI后，ObR−/−小鼠有更大的心功能障碍，左心室扩张和氧化应激水平。ObR−/−小鼠心脏损伤的这些更差指标与信号转导和转录激活因子（STAT）3、磷脂酰肌醇-3-激酶（PI 3 K）和Akt信号转导减弱、丙二酰辅酶A含量降低以及线粒体丙酮酸脱氢酶和电子传递复合物I、II和IV活性降低有关。此外，ObR−/−小鼠在MI后保持了较高的心脏脂肪酸氧化率，而ObR+/+小鼠表现出从脂肪酸氧化到葡萄糖代谢的转变。心肌梗死后ObR−/−小鼠心脏STAT 3、PI 3 K和Akt活性以及线粒体功能的恢复是通过睫状神经营养因子（CNTF）完成的，CNTF是一种既定的STAT 3激活剂，在心肌梗死后立即给药。此外，CNTF治疗导致心脏结构和功能损伤减轻，氧化应激水平减弱，并挽救了梗死ObR−/−心脏的葡萄糖代谢。这些数据表明，受损的心脏瘦素信号导致在面对心脏应激时葡萄糖利用的代谢不稳定性，以及MI后更高的发病率。此外，这些研究表明，在瘦素抵抗的心脏中，通过CNTF介导的存活激酶的激活，心脏葡萄糖代谢可以恢复，导致MI后多种结构和功能结局的改善。
In the normal heart, leptin modulates cardiac metabolism. It is unknown, however, what effect leptin has on cardiac metabolism and outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that leptin signaling increases glucose metabolism and attenuates injury in the acutely infarcted heart. Mice with (ObR+/+) and without (ObR−/−) cardiomyocyte specific expression of leptin receptor (ObR) were randomly assigned to experimental MI or sham procedure, and studied 3days later. ObR+/+and ObR−/−sham mice were not significantly different in any measured outcome. However, after MI, ObR−/−mice had greater cardiac dysfunction, left ventricular dilation, and levels of oxidative stress. These worse indices of cardiac injury in ObR−/−mice were associated with attenuated signal transducer and activator of transcription (STAT) 3, phosphatidylinositol-3-kinase (PI3K), and Akt signaling, decreased malonyl CoA content, and reduced mitochondrial pyruvate dehydrogenase and electron transport Complex I, II and IV activities. Furthermore, ObR−/−mice maintained high rates of cardiac fatty acid oxidation after MI, whereas ObR+/+mice demonstrated a switch away from fatty acid oxidation to glucose metabolism. Restoration of cardiac STAT3, PI3K and Akt activity and mitochondrial function in ObR−/−mice post-MI was accomplished by ciliary neurotrophic factor (CNTF), an established STAT3 activator, administered immediately after MI. Moreover, CNTF therapy resulted in mitigation of cardiac structural and functional injury, attenuated levels of oxidative stress, and rescued glucose metabolism in the infarcted ObR−/−heart. These data demonstrate that impaired cardiac leptin signaling results in metabolic inflexibility for glucose utilization in the face of cardiac stress, and greater morbidity after MI. Further, these studies show that cardiac glucose metabolism can be restored in leptin-resistant hearts by CNTF-mediated activation of survival kinases, resulting in multiple improved structural and functional outcomes post-MI.