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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes.
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Dual effect of the heart-targeting cytokine cardiotrophin-1 on glucose transport in cardiomyocytes.

机译：靶向心脏的细胞因子心肌营养素1对心肌细胞葡萄糖转运的双重作用。

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Cardiotrophin-1 (CT-1) is a heart-targeting cytokine that is increased in the metabolic syndrome due to overexpression in the adipocytes. The effects of CT-1 on cardiomyocyte substrate metabolism remain unknown. We therefore determined the effects of CT-1 on basal and stimulated glucose transport in cardiomyocytes exposed to a low dose (1nM) or a high dose (10nM). Dose-response curves for insulin showed that 1nM CT-1 reduced insulin responsiveness, while 10nM CT-1 increased insulin responsiveness. In either condition insulin sensitivity was unaffected. Similarly 1nM CT-1 reduced the stimulation of glucose transport in response to metabolic stress, induced by the mitochondrial poison oligomycin, while 10nM CT-1 increased this response. Reduction of stimulated glucose transport by 1nM CT-1 was associated with overexpression of SOCS-3, a protein known to hinder proximal insulin signaling, and increased phosphorylation of STAT5. In cardiomyocytes exposed to 1nM CT-1 there was also reduced phosphorylation of Akt and AS160 in response to insulin, and of AMPK in response to oligomycin. Insulin-stimulated glucose transport and signaling were restored by inhibition of STAT5 activity. On the other hand in cardiomyocytes exposed to 10nM CT-1 there was increased phosphorylation of the AS160 and Akt in response to insulin. Most importantly, basal and oligomycin-stimulated phosphorylation of AMPK was markedly increased in cardiomyocytes exposed to 10nM CT-1. The enhancement of basal and stimulated-glucose transport was abolished in cardiomyocytes treated with the calmodulin-dependent kinase II (CaMKII) inhibitor KN93, and so was AMPK phosphorylation. This suggests that activation of CaMKII mediates activation of AMPK by a high dose of CT-1 independently of metabolic stress. Our results point to a role for CT-1 in the regulation of myocardial glucose metabolism and implicate entirely separate mechanisms in the inhibitory or stimulatory effects of CT-1 on glucose transport at low or high concentrations respectively.
机译：心肌营养素1（CT-1）是一种针对心脏的细胞因子，由于脂肪细胞的过度表达，在代谢综合征中增加。 CT-1对心肌细胞底物代谢的影响仍然未知。因此，我们确定了CT-1对暴露于低剂量（1nM）或高剂量（10nM）的心肌细胞的基础和刺激葡萄糖转运的影响。胰岛素的剂量反应曲线显示1nM CT-1降低了胰岛素反应性，而10nM CT-1则增加了胰岛素反应性。在任何一种情况下，胰岛素敏感性均不受影响。同样，1nM CT-1减少了响应线粒体毒素寡聚霉素诱导的代谢应激而引起的葡萄糖转运刺激，而10nM CT-1则增加了这种反应。 1nM CT-1减少刺激的葡萄糖转运与SOCS-3（一种已知会阻碍近端胰岛素信号传导的蛋白）的过表达以及STAT5的磷酸化增加有关。在暴露于1nM CT-1的心肌细胞中，响应胰岛素，Akt和AS160的磷酸化也降低，响应寡霉素响应的AMPK的磷酸化也降低。胰岛素刺激的葡萄糖转运和信号传导通过抑制STAT5活性得以恢复。另一方面，在暴露于10nM CT-1的心肌细胞中，响应胰岛素，AS160和Akt的磷酸化增加。最重要的是，在暴露于10nM CT-1的心肌细胞中，AMPK的基础和寡霉素刺激的磷酸化显着增加。在用钙调蛋白依赖性激酶II（CaMKII）抑制剂KN93处理的心肌细胞中，基础和刺激葡萄糖转运的增强被消除，AMPK磷酸化也被消除。这表明CaMKII的激活通过高剂量的CT-1介导了AMPK的激活，而与代谢应激无关。我们的结果指出CT-1在调节心肌葡萄糖代谢中的作用，并且在低浓度或高浓度下CT-1对葡萄糖转运的抑制或刺激作用中包含了完全独立的机制。

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