Endothelial Cell-Derived Nitric Oxide Enhances Aerobic Glycolysis in Astrocytes via HIF-1α-Mediated Target Gene Activation
Endothelial Cell-Derived Nitric Oxide Enhances Aerobic Glycolysis in Astrocytes via HIF-1α-Mediated Target Gene Activation
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DOI：
10.1523/jneurosci.0879-12.2012
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发表时间：
2012-07-11
影响因子：
5.3
通讯作者：
Joehren, Olaf
中科院分区：
文献类型：
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作者：
Brix, Britta;Mesters, Jeroen R.;Joehren, Olaf
星形胶质细胞表现出显著的糖酵解活性，但这种代谢特征是否受到细胞间通讯的影响尚不清楚。原代培养的小鼠皮质星形胶质细胞用一氧化氮(NO)供体DetaNONOate处理后，编码各种糖酵解酶以及葡萄糖和乳酸转运蛋白的基因表达随时间而增加。这种作用依赖于缺氧诱导因子HIF-1α，该因子稳定并移位到细胞核以发挥其转录调节作用。NO的作用依赖于PI3K/Akt/mTOR和MEK信号通路，需要COX的激活，但不依赖于可溶性鸟苷环化酶途径。此外，作为NO处理的结果，星形胶质细胞乳酸的产生和释放被证明是明显的，这可以通过下调HIF-1α来阻止。几种脑细胞类型代表了一氧化氮的可能来源。研究发现，在培养过程中，表达内皮型一氧化氮合酶(ENOS)亚型的内皮细胞结构性地产生最多的NO。星形胶质细胞与原代培养的脑血管内皮细胞共培养时，HIF-1α趋于稳定，葡萄糖转运蛋白-1、己糖激酶-2和单羧酸转运蛋白-4的表达增强，乳酸生成增加。这种作用可被一氧化氮合酶抑制剂L-NAME抑制，当星形胶质细胞与原代培养的皮质神经元共同培养时，这种作用不明显。我们的研究结果表明，内皮细胞来源的NO参与了星形胶质细胞HIF-1α激活所介导的高糖酵解活性的维持。
Astrocytes exhibit a prominent glycolytic activity, but whether such a metabolic profile is influenced by intercellular communication is unknown. Treatment of primary cultures of mouse cortical astrocytes with the nitric oxide (NO) donor DetaNONOate induced a time-dependent enhancement in the expression of genes encoding various glycolytic enzymes as well as transporters for glucose and lactate. Such an effect was shown to be dependent on the hypoxia-inducible factor HIF-1 alpha, which is stabilized and translocated to the nucleus to exert its transcriptional regulation. NO action was dependent on both the PI3K/Akt/mTOR and MEK signaling pathways and required the activation of COX, but was independent of the soluble guanylate cyclase pathway. Furthermore, as a consequence of NO treatment, an enhanced lactate production and release by astrocytes was evidenced, which was prevented by downregulating HIF-1 alpha. Several brain cell types represent possible sources of NO. It was found that endothelial cells, which express the endothelial NO synthase (eNOS) isoform, constitutively produced the largest amount of NO in culture. When astrocytes were cocultured with primary cultures of brain vascular endothelial cells, stabilization of HIF-1 alpha and an enhancement in glucose transporter-1, hexokinase-2, and monocarboxylate transporter-4 expression as well as increased lactate production was found in astrocytes. This effect was inhibited by the NOS inhibitor L-NAME and was not seen when astrocytes were cocultured with primary cultures of cortical neurons. Our findings suggest that endothelial cell-derived NO participates to the maintenance of a high glycolytic activity in astrocytes mediated by astrocytic HIF-1 alpha activation.