Freeman Robert S, Barone Maria Cecilia
Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Curr Drug Targets CNS Neurol Disord. 2005 Feb;4(1):85-92. doi: 10.2174/1568007053005154.
Hypoxia occurs when oxygen availability drops below the levels necessary to maintain normal rates of metabolism. Because of its high metabolic activity, the brain is highly sensitive to hypoxia. Severe or prolonged oxygen deprivation in the brain contributes to the damage associated with stroke and a variety of other neuronal disorders. Conversely, the extreme hypoxic environment found in the core of many brain tumors supports the growth of the tumor and the survival of tumor cells. Normal cells exposed to transient or moderate hypoxia are generally able to adapt to the hypoxic conditions largely through activation of the hypoxia-inducible transcription factor HIF. HIF-regulated genes encode proteins involved in energy metabolism, cell survival, erythropoiesis, angiogenesis, and vasomotor regulation. In many instances of hypoxia or hypoxia and ischemia, the induction of HIF target genes may be beneficial. When these same insults occur in tissues that are normally poorly vascularized, such as the retina and the core of solid tumors, induction of the same HIF target genes can promote disease. Major new insights into the molecular mechanisms that regulate the oxygen-sensitivity of HIF, and in the development of compounds with which to manipulate HIF activity, are forcing serious consideration of HIF as a therapeutic target for diverse CNS disorders associated with hypoxia.
当氧气供应降至维持正常代谢率所需水平以下时，就会发生缺氧。由于大脑具有高代谢活性，因此对缺氧高度敏感。大脑中严重或长期的氧剥夺会导致与中风及多种其他神经疾病相关的损伤。相反，在许多脑肿瘤核心部位发现的极端缺氧环境会促进肿瘤生长和肿瘤细胞存活。暴露于短暂或中度缺氧的正常细胞通常能够通过激活缺氧诱导转录因子HIF在很大程度上适应缺氧条件。HIF调控的基因编码参与能量代谢、细胞存活、红细胞生成、血管生成和血管舒缩调节的蛋白质。在许多缺氧或缺氧与缺血的情况下，HIF靶基因的诱导可能是有益的。当这些相同的损伤发生在正常血管化较差的组织中，如视网膜和实体瘤核心时，相同HIF靶基因的诱导会促进疾病发展。对调节HIF氧敏感性的分子机制以及用于操纵HIF活性的化合物开发的重大新见解，促使人们认真考虑将HIF作为与缺氧相关的多种中枢神经系统疾病的治疗靶点。
