Laboratory of Regulation of Brain Neuron Functions, Pavlov Institute of Physiology, Russian Academy of Sciences, Saint-Petersburg, Russia.
Department of Biochemistry, Faculty of Biology, Saint-Petersburg State University, Saint-Petersburg, Russia.
J Neurochem. 2019 Sep;150(6):645-647. doi: 10.1111/jnc.14822. Epub 2019 Aug 2.
Hypoxia-inducible factor (HIF-1) as the primary factor mediating gene-dependent cellular responses to hypoxia represents an attractive target for the therapeutic interventions. The current Editorial comments on an as yet underestimated facet of HIF-1-related research. The activity of HIF-1 is being regulated by the availability of its α-subunit HIF-1α, which undergoes quick degradation. The process of degradation is initiated by prolyl 4-hydroxylase (PHD). PHD is an oxygen-dependent enzyme and therefore is inactivated in hypoxia, in turn resulting in HIF-1α stabilization, its dimerization with HIF-1β subunit thereby producing the transcriptionally active factor. It has been suggested that pharmacological inhibition of PHD activity might give the same results. Indeed, a large body of evidence on beneficial effects of PHD inhibitors has been accumulated in multiple laboratory and clinical trials. In addition to them, a paper by Li and colleagues published in this issue of Journal of Neurochemistry also reports that inhibition of PHD by adaptaquin reduces hypoxic-ischemic brain injury in a neonatal mouse model. When dissecting the underlying molecular mechanisms, Li and colleagues surprisingly found that the observed effects appear to be independent of HIF-1. These findings draw attention back to the question about possible HIF-1 effects independent of PHD inhibitors, which has been raised several years ago but has not received sufficient attention so far, and is being discussed in this Editorial. One of the possible mechanisms might be ascribed to the ferroptosis pathway affected by PHD inhibitors but this question needs further careful studies, as well as clarification of other mechanisms possibly involved. Even if they represent a prospective therapeutic strategy, the lack of current knowledge about endogenous targets of PHD inhibitors, except for PHD, calls for a careful and balanced approach toward their clinical use.
缺氧诱导因子 (HIF-1) 作为介导细胞对缺氧的基因依赖性反应的主要因子，是治疗干预的一个有吸引力的靶点。本期社论评论了 HIF-1 相关研究中一个尚未被充分认识的方面。HIF-1 的活性受到其α亚基 HIF-1α的可用性的调节，HIF-1α 迅速降解。降解过程由脯氨酰 4-羟化酶 (PHD) 启动。PHD 是一种氧依赖性酶，因此在缺氧时失活，从而导致 HIF-1α 稳定，与 HIF-1β 亚基二聚化，从而产生转录活性因子。有人提出，PHD 活性的药理学抑制可能会产生相同的效果。事实上，大量的证据表明 PHD 抑制剂具有有益的效果，已经在多个实验室和临床试验中得到了积累。除了这些，Li 及其同事在本期《神经化学杂志》上发表的一篇论文也报道了 adaptaquin 抑制 PHD 可减少新生小鼠模型中的缺氧缺血性脑损伤。在剖析潜在的分子机制时，Li 及其同事令人惊讶地发现，观察到的效果似乎与 HIF-1 无关。这些发现使人们再次关注 HIF-1 可能独立于 PHD 抑制剂的作用的问题，这个问题几年前就已经提出，但到目前为止还没有得到足够的重视，本期社论对此进行了讨论。其中一个可能的机制可以归因于 PHD 抑制剂影响的铁死亡途径，但这个问题需要进一步仔细研究，以及澄清可能涉及的其他机制。即使它们代表了一种有前景的治疗策略，目前缺乏对 PHD 抑制剂的内源性靶点（除了 PHD 之外）的了解，呼吁对其临床应用采取谨慎和平衡的方法。
