Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia.
Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia.
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心脏磷酸酶缺陷的 6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶会增加糖酵解、肥大和心肌细胞对缺氧的抵抗力。
DOI：
10.1152/ajpheart.91501.2007
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Epstein,PaulN
中科院分区：
文献类型：
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作者：
Wang,Qianwen;Donthi,RajakumarV;Wang,Jianxun;Lange,AlexJ;Watson,LewisJ;Jones,StevenP;Epstein,PaulN
在缺血和心力衰竭期间，心脏糖酵解增加。为了了解这对心脏是有益的还是有害的，我们在转基因小鼠中通过磷酸酶缺陷型6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶（PFK-2）的心脏特异性过表达来长期提高糖酵解。PFK-2控制果糖-2，6-二磷酸（Fru-2，6-P2）的水平，这是磷酸果糖激酶和糖酵解的重要调节剂。转基因小鼠的Fru-2，6-P2水平升高了三倍以上。磷酸果糖激酶上游的心脏代谢物显著减少，正如磷酸果糖激酶激活所预期的那样。在灌注的心脏中，转基因引起糖酵解的显著增加，而糖酵解对棕榈酸酯的抑制不太敏感。相反，棕榈酸酯的氧化减少了接近50%。糖酵解的升高使分离的心肌细胞对缺氧引起的收缩抑制具有高度抵抗性，但在体内转基因对缺血再灌注损伤没有影响。转基因心脏表现出病理学变化：心脏重量/体重比增加17%，心肌细胞长度增加，心脏纤维化增加。然而，转基因并没有改变胰岛素敏感性。这些结果表明，糖酵解的升高提供了对抗缺氧的急性益处，但糖酵解的慢性增加或脂肪酸氧化的减少干扰了正常的心脏代谢，这可能对心脏有害。
During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.