Division of Medicine, Rayne Institute, University College London, University Street, London, United Kingdom.
Antioxid Redox Signal. 2010 Apr;12(4):459-80. doi: 10.1089/ars.2009.2870.
Abstract Ischemic stroke is a major cause of death worldwide, and current therapeutic options are very limited. Preconditioning with an ischemic or hypoxic insult is beneficial in experimental models of ischemic stroke. Ischemia/hypoxia results in activation of numerous transcription factors, including hypoxia inducible factor (HIF), which is a master regulator of oxygen homeostasis. HIF activation induces a diverse range of target genes, encompassing a wide variety of cellular processes; including angiogenesis, energy metabolism, cell survival, radical production/scavenging, iron metabolism, stem cell homing, and differentiation. Inhibition of HIF prolyl hydroxylase domain (PHD) enzymes results in activation of HIF and is likely to mimic, at least in part, the effects of hypoxia preconditioning. A caveat is that not all consequences of HIF activation will be beneficial and some could even be deleterious. Nevertheless, PHD inhibitors may be therapeutically useful in the treatment of stroke. Prototype PHD inhibitors have shown promising results in preclinical models.
摘要 缺血性脑卒中是全球范围内主要的致死病因，目前的治疗选择非常有限。在缺血性脑卒中的实验模型中，缺血或缺氧预处理具有有益作用。缺血/缺氧导致许多转录因子激活，包括缺氧诱导因子 (HIF)，它是氧平衡的主要调节因子。HIF 的激活诱导了广泛的靶基因，涵盖了各种细胞过程；包括血管生成、能量代谢、细胞存活、自由基产生/清除、铁代谢、干细胞归巢和分化。抑制 HIF 脯氨酰羟化酶结构域 (PHD) 酶会导致 HIF 的激活，并且可能至少在一定程度上模拟缺氧预处理的作用。但需要注意的是，HIF 激活的并非所有后果都有益，有些甚至可能有害。尽管如此，PHD 抑制剂在脑卒中的治疗中可能具有治疗作用。原型 PHD 抑制剂在临床前模型中显示出了有前景的结果。
