Brain-specific knock-out of hypoxia-inducible factor-1α reduces rather than increases hypoxic-ischemic damage
Brain-specific knock-out of hypoxia-inducible factor-1α reduces rather than increases hypoxic-ischemic damage
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DOI：
10.1523/jneurosci.4555-04.2005
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发表时间：
2005-04-20
影响因子：
5.3
通讯作者：
Barlow, C
中科院分区：
文献类型：
--
作者：
Helton, R;Cui, J;Barlow, C
低氧诱导因子-1α(HIF-1α)通过调节糖酵解、红细胞生成、血管生成和儿茶酚胺代谢等重要基因的表达，在细胞和全身O-2动态平衡中发挥重要作用。在中风等病理生理条件下，它也被认为是细胞对缺氧和缺血反应的关键组成部分。为了阐明HIF-1α在大脑中的功能，我们将大脑晚期HIF-1α缺失的成年小鼠暴露在低氧损伤中。与预期相反，HIF-1α缺陷小鼠的大脑受到保护，免受缺氧诱导的细胞死亡。这些令人惊讶的发现表明，降低HIF-1α水平可以起到神经保护作用。基因芯片表达分析显示，与预期相反，大多数低氧依赖的基因表达变化没有改变，而在HIF-1α缺陷小鼠中观察到凋亡基因的特异性下调。虽然HIF-1α在体外、癌症模型和慢性预适应范例中的作用已被广泛表征，但这是第一次在体内评估HIF-1α在急性缺氧/缺血反应中的作用。我们的数据表明，在急性缺氧中，在HIF-1α缺陷小鼠中发现的神经保护与HIF-1α作为促凋亡和功能丧失导致神经保护的主要作用在力学上是一致的。此外，我们的数据表明，在排除HIF-1α后，功能冗余发展，导致调节大多数其他先前表征的HIF依赖基因的基因表达被保留。
Hypoxia-inducible factor-1 alpha(HIF-1 alpha) plays an essential role in cellular and systemic O-2 homeostasis by regulating the expression of genes important in glycolysis, erythropoiesis, angiogenesis, and catecholamine metabolism. It is also believed to be a key component of the cellular response to hypoxia and ischemia under pathophysiological conditions, such as stroke. To clarify the function of HIF-1 alpha in the brain, we exposed adult mice with late-stage brain deletion of HIF-1 alpha to hypoxic injuries. Contrary to expectations, the brains from the HIF-1 alpha-deficient mice were protected from hypoxia-induced cell death. These surprising findings suggest that decreasing the level of HIF-1 alpha can be neuroprotective. Gene chip expression analysis revealed that, contrary to expectations, the majority of hypoxia-dependent gene-expression changes were unaltered, whereas a specific downregulation of apoptotic genes was observed in the HIF-1 alpha-deficient mice. Although the role of HIF-1 alpha has been extensively characterized in vitro, in cancer models, and in chronic preconditioning paradigms, this is the first study to evaluate the role of HIF-1 alpha in vivo in the brain in response to acute hypoxia/ischemia. Our data suggest, that in acute hypoxia, the neuroprotection found in the HIF-1 alpha-deficient mice is mechanistically consistent with a predominant role of HIF-1 alpha as proapoptotic and loss of function leads to neuroprotection. Furthermore, our data suggest that functional redundancy develops after excluding HIF-1 alpha, leading to the preservation of gene expression regulating the majority of other previously characterized HIF-dependent genes.