Li Tingting, Xu Jie, Qin Xinghua, Hou Zuoxu, Guo Yongzheng, Liu Zhenhua, Wu Jianjiang, Zheng Hong, Zhang Xing, Gao Feng
School of Aerospace Medicine, Fourth Military Medical University, Xi'an, China; and.
Department of Anesthesiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Am J Physiol Endocrinol Metab. 2017 Nov 1;313(5):E577-E585. doi: 10.1152/ajpendo.00014.2017. Epub 2017 Mar 21.
Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia-reperfusion (I/R) injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. We found that glucose uptake was remarkably diminished in the myocardium following reperfusion in Sprague-Dawley rats as detected by F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by threefold and GLUT4 translocation remained unchanged compared with those of sham-treated rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated I/R injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, whereas its knockdown increased glucose uptake, suggesting that PDK4 has a role in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial I/R. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in the myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial I/R injury.
心肌再灌注会降低葡萄糖氧化，并使葡萄糖氧化与糖酵解解偶联。增加葡萄糖氧化的疗法可减轻心肌缺血-再灌注（I/R）损伤。然而，再灌注期间葡萄糖摄取的调节仍知之甚少。我们发现，用F标记和荧光标记的葡萄糖类似物检测，在Sprague-Dawley大鼠再灌注后心肌中的葡萄糖摄取显著减少，尽管与假手术处理的大鼠相比，葡萄糖转运蛋白1（GLUT1）上调了三倍，且GLUT4转位未发生变化。葡萄糖摄取减少伴随着葡萄糖氧化受到抑制。有趣的是，通过抑制丙酮酸脱氢酶激酶4（PDK4，一种葡萄糖氧化的限速酶）来刺激葡萄糖氧化，可增加葡萄糖摄取并减轻I/R损伤。新生心肌细胞的体外数据表明，PDK4过表达会降低葡萄糖摄取，而其敲低则会增加葡萄糖摄取，这表明PDK4在调节葡萄糖摄取中发挥作用。此外，抑制PDK4可增加心肌葡萄糖摄取，并伴随心肌I/R后心脏胰岛素敏感性的增强。这些结果表明，由PDK4介导的葡萄糖氧化受抑制导致再灌注后心肌中葡萄糖摄取减少，而增加葡萄糖摄取可发挥心脏保护作用。这些发现表明，通过PDK4刺激葡萄糖氧化可能是改善心肌I/R损伤恢复的有效方法。
