Cardiac expression of kinase-deficient 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity
Cardiac expression of kinase-deficient 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity
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DOI：
10.1074/jbc.m405510200
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发表时间：
2004-11-12
影响因子：
4.8
通讯作者：
Epstein, PN
中科院分区：
文献类型：
--
作者：
Donthi, RV;Ye, G;Epstein, PN
糖酵解对于心脏代谢很重要，糖酵解减少可能导致糖尿病性心肌病。为了了解其独立于糖尿病或缺氧损伤的作用，我们通过激酶缺陷的 6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶 (kd-PFK-2) 的心脏特异性过度表达来调节糖酵解。 PFK-2 控制果糖 2,6-二磷酸 (Fru-2,6-P-2) 的水平，果糖 2,6-P-2 是糖酵解的重要调节剂。转基因小鼠的 Fru-2,6-P-2 水平降低了 2 倍以上。心脏重量/体重比表明轻度肥厚。胶原蛋白的天狼星红染色显着增加。我们观察到葡萄糖 6-磷酸和果糖 6-磷酸水平升高了 2 倍，而果糖 1,6-二磷酸水平降低了 2 倍。磷酸果糖激酶上方的糖酵解分支途径被激活，如 UDP-N-乙酰氨基葡萄糖和糖原升高超过 2 倍所示。 kd-PFK-2 转基因显着抑制灌注心脏中的糖酵解。胰岛素对代谢的刺激和 Akt 磷酸化急剧减少。此外，在基础和低氧孵育期间，分离的心肌细胞的收缩性受损。目前的研究表明，激酶缺陷型 PFK-2 的心脏过度表达会减少心脏糖酵解，从而对心脏产生负面影响，包括肥大、纤维化和心肌细胞功能降低。此外，对胰岛素的代谢和信号反应显着降低。
Glycolysis is important to cardiac metabolism and reduced glycolysis may contribute to diabetic cardiomyopathy. To understand its role independent of diabetes or hypoxic injury, we modulated glycolysis by cardiac-specific overexpression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (kd-PFK-2). PFK-2 controls the level of fructose 2,6-bisphosphate (Fru-2,6-P-2), an important regulator of glycolysis. Transgenic mice had over 2-fold reduced levels of Fru-2,6-P-2. Heart weight/body weight ratio indicated mild hypertrophy. Sirius red staining for collagen was significantly increased. We observed a 2-fold elevation in glucose 6-phosphate and fructose 6-phosphate levels, whereas fructose 1,6-bisphosphate was reduced 2-fold. Pathways branching off of glycolysis above phosphofructokinase were activated as indicated by over 2-fold elevated UDP-N-acetylglucosamine and glycogen. The kd-PFK-2 transgene significantly inhibited glycolysis in perfused hearts. Insulin stimulation of metabolism and Akt phosphorylation were sharply reduced. In addition, contractility of isolated cardiomyocytes was impaired during basal and hypoxic incubations. The present study shows that cardiac overexpression of kinase-deficient PFK-2 reduces cardiac glycolysis that produced negative consequences to the heart including hypertrophy, fibrosis, and reduced cardiomyocyte function. In addition, metabolic and signaling responses to insulin were significantly decreased.