Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase
Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase
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DOI：
10.1165/rcmb.2013-0187oc
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发表时间：
2014-06-01
影响因子：
6.4
通讯作者：
Black, Stephen M.
中科院分区：
文献类型：
--
作者：
Sun, Xutong;Kumar, Sanjiv;Black, Stephen M.
最近的研究表明，在肺动脉高压（PH）的发展过程中，肺内皮细胞中存在从氧化磷酸化到糖酵解的转变。然而，这种现象背后的机制尚未阐明。内皮素（ET）-1，内皮源性血管收缩肽，增加PH，并已被证明在氧化应激与PH。因此，在这项研究中，我们调查是否有一个潜在的联系ET-1和线粒体重塑之间的增加。我们的数据表明，ET-1诱导内皮型一氧化氮合酶（eNOS）的再分配从质膜到线粒体在肺动脉内皮细胞，这是依赖于eNOS解偶联。我们还发现，ET-1干扰肉毒碱代谢，导致线粒体生物能量衰减。然而，由于糖酵解的代偿性增加，ATP水平没有变化。进一步的机制研究表明，ET-1介导eNOS的再分布通过蛋白激酶C δ磷酸化eNOS的Thr 495。此外，糖酵解开关似乎依赖于脑源性活性氧，导致缺氧诱导因子信号转导的激活。最后，细胞培养数据在体内使用野百合碱大鼠PH模型得到证实。因此，我们得出结论，ET-1诱导肺动脉内皮细胞糖酵解开关通过重新分配的未偶联eNOS的线粒体，并防止这一事件可能是一种治疗PH的方法。
Recent studies have indicated that, during the development of pulmonary hypertension (PH), there is a switch from oxidative phosphorylation to glycolysis in the pulmonary endothelium. However, the mechanisms underlying this phenomenon have not been elucidated. Endothelin (ET)-1, an endothelial-derived vasoconstrictor peptide, is increased in PH, and has been shown to play an important role in the oxidative stress associated with PH. Thus, in this study, we investigated whether there was a potential link between increases in ET-1 and mitochondrial remodeling. Our data indicate that ET-1 induces the redistribution of endothelial nitric oxide synthase (eNOS) from the plasma membrane to the mitochondria in pulmonary arterial endothelial cells, and that this was dependent on eNOS uncoupling. We also found that ET-1 disturbed carnitine metabolism, resulting in the attenuation of mitochondrial bioenergetics. However, ATP levels were unchanged due to a compensatory increase in glycolysis. Further mechanistic investigations demonstrated that ET-1 mediated the redistribution of eNOS via the phosphorylation of eNOS at Thr495 by protein kinase C delta. In addition, the glycolytic switch appeared to be dependent on mitochondrial-derived reactive oxygen species that led to the activation of hypoxia-inducible factor signaling. Finally, the cell culture data were confirmed in vivo using the monocrotaline rat model of PH. Thus, we conclude that ET-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the redistribution of uncoupled eNOS to the mitochondria, and that preventing this event may be an approach for the treatment of PH.