选择性抑制缺氧诱导因子 (HIF) 脯氨酰羟化酶 1 通过 HIF 和 CREB 非依赖性途径介导对常氧氧化死亡的神经保护作用。,Journal of Neuroscience

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选择性抑制缺氧诱导因子 (HIF) 脯氨酰羟化酶 1 通过 HIF 和 CREB 非依赖性途径介导对常氧氧化死亡的神经保护作用。
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2009-07-08 , DOI: 10.1523/jneurosci.1779-09.2009
Ambreena Siddiq ₁ , Leila R Aminova , Carol M Troy , Kyungsun Suh , Zachary Messer , Gregg L Semenza , Rajiv R Ratan

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从心血管疾病到中风、脊髓损伤、神经变性，甚至衰老，氧化应激都会导致组织损伤。然而，抗氧化剂在人类疾病中的功效充其量只是好坏参半。我们需要更好地了解已建立的抗氧化剂对抗氧化应激的机制。铁螯合剂是神经和非神经组织中公认的氧化死亡抑制剂，但它们的确切作用机制仍然难以捉摸。普遍但未完全证实的观点是，铁螯合剂通过抑制芬顿化学和高反应性羟基自由基的形成来防止氧化损伤。在这里，我们表明铁螯合通过抑制缺氧诱导因子脯氨酰 4-羟化酶同种型 1 (PHD1) 来保护，而出乎意料的是，铁和 2-酮戊二酸依赖性双加氧酶。PHD1 及其同种型 2 和 3 以稳定参与缺氧适应的转录调节因子而闻名，例如 HIF-1alpha 和 cAMP 反应元件结合蛋白 (CREB)。然而我们发现，即使直接抑制 HIF-1alpha 和 CREB，全局缺氧诱导因子 (HIF)-PHD 抑制也能保护神经元。此外，即使在 HIF-2alpha 水平降低的情况下，两种全球 HIF-PHD 抑制剂仍继续具有神经保护作用，这本身会增加神经元对氧化应激的敏感性。最后，对 PHD1 而非同工型 PHD2 或 PHD3 的 RNA 干扰可防止氧化死亡，而与 HIF 激活无关。一起，这些研究表明，铁螯合剂可以通过选择性抑制 PHD1 但不依赖于 HIF-1alpha 和 CREB 来预防常氧氧化性神经元死亡；并且 HIF-2alpha，而不是 HIF-1alpha，调节对常氧氧化神经元死亡的易感性。

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Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways.

Oxidative stress contributes to tissue injury in conditions ranging from cardiovascular disease to stroke, spinal cord injury, neurodegeneration, and perhaps even aging. Yet the efficacy of antioxidants in human disease has been mixed at best. We need a better understanding of the mechanisms by which established antioxidants combat oxidative stress. Iron chelators are well established inhibitors of oxidative death in both neural and non-neural tissues, but their precise mechanism of action remains elusive. The prevailing but not completely substantiated view is that iron chelators prevent oxidative injury by suppressing Fenton chemistry and the formation of highly reactive hydroxyl radicals. Here, we show that iron chelation protects, rather unexpectedly, by inhibiting the hypoxia-inducible factor prolyl 4-hydroxylase isoform 1 (PHD1), an iron and 2-oxoglutarate-dependent dioxygenase. PHD1 and its isoforms 2 and 3 are best known for stabilizing transcriptional regulators involved in hypoxic adaptation, such as HIF-1alpha and cAMP response element-binding protein (CREB). Yet we find that global hypoxia-inducible factor (HIF)-PHD inhibition protects neurons even when HIF-1alpha and CREB are directly suppressed. Moreover, two global HIF-PHD inhibitors continued to be neuroprotective even in the presence of diminished HIF-2alpha levels, which itself increases neuronal susceptibility to oxidative stress. Finally, RNA interference to PHD1 but not isoforms PHD2 or PHD3 prevents oxidative death, independent of HIF activation. Together, these studies suggest that iron chelators can prevent normoxic oxidative neuronal death through selective inhibition of PHD1 but independent of HIF-1alpha and CREB; and that HIF-2alpha, not HIF-1alpha, regulates susceptibility to normoxic oxidative neuronal death.

更新日期：2019-11-01

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