Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia.
Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia.
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DOI：
10.1007/s12975-013-0312-z
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发表时间：
2014-02
影响因子：
6.9
通讯作者：
Tang, Jiping
中科院分区：
文献类型：
--
作者：
Souvenir, Rhonda;Flores, Jerry J.;Ostrowski, Robert P.;Manaenko, Anatol;Duris, Kamil;Tang, Jiping
缺氧诱导因子（Hypoxia inducible factor， HIF）-1α是调控缺氧相关基因的中心转录因子。促红细胞生成素（EPO）是一种造血生长因子，在缺氧/缺血时增加氧的可用性，并与缺氧缺血后脑卒中实验室模型的神经保护有关。然而，EPO未能在临床环境中转化。因此，阐明epo诱导的神经保护机制至关重要。我们的初步研究表明，EPO作为缺氧诱导因子（HIF）的下游基因，在体外缺氧缺血模型中以剂量依赖的方式抑制HIF-1α。本研究旨在阐明epo诱导的HIF-1α抑制和随后的细胞存活/神经保护的主要介质。采用神经生长因子（NGF）诱导大鼠嗜铬细胞瘤（PC-12）细胞缺氧缺血模型。在OGD期间，在EPO或PHD-2抑制剂存在和不存在的情况下，评估HIF-1α、HIF-2α和PHD-2的表达、HIF-1α和脯氨酸羟化酶（PHD-2） mRNA水平、MMP-9和细胞死亡情况。我们的研究结果表明，EPO处理导致PHD-2转录和翻译增加，抑制HIF-1α表达，活性氧（ROS）形成和基质金属蛋白酶(MMP)-9活性，导致OGD后细胞存活增加。我们还观察到epo诱导的细胞存活/神经保护被PHD-2的siRNA沉默逆转。由此得出结论，在体外缺氧缺血模型中，PHD-2是epo诱导的HIF-1α抑制和随后的神经保护的关键介质。
Hypoxia inducible factor (HIF)-1α is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia. Erythropoietin (EPO), a hematopoietic growth factor, increases oxygen availability during hypoxia/ischemia and is associated with neuroprotection following hypoxia ischemia in laboratory models of stroke. However, EPO has failed to translate in a clinical setting. Thus it is critical to elucidate the key players in EPO-induced neuroprotection. Our preliminary studies have shown that EPO, as a downstream gene of hypoxia inducible factor (HIF), inhibits HIF-1α in a dose-dependent manner in an in-vitro model of hypoxia ischemia. This study is designed to elucidate the primary mediator of EPO-induced HIF-1α inhibition and subsequent cell survival/neuroprotection. Oxygen and glucose deprivation (OGD) of nerve growth factor (NGF) differentiated rat pheochromocytoma (PC-12) cells were used to model hypoxia ischemia in an in vitro environment. The profile of HIF-1α, HIF-2α and PHD-2 expression, HIF-1α and prolyl hydroxylase (PHD-2) mRNA levels, MMP-9 and cell death was evaluated in the presence and absence of either EPO or PHD-2 inhibitor during OGD. Our findings showed that EPO treatment resulted in an increase in PHD-2 transcription and translation, inhibition of HIF-1α expression, reactive oxygen species (ROS) formation and matrix metalloproteinase (MMP)-9 activity, resulting in increased cell survival after OGD. We also observed that EPO-induced cell survival/neuroprotection was reversed by siRNA silencing of PHD-2. This led to the conclusion that PHD-2 is a key mediator of EPO-induced HIF-1α inhibition and subsequent neuroprotection in an in vitro model of hypoxia ischemia.
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