Wang Xinghe, Deng Jixian, Boyle David W, Zhong Jin, Lee Wei-Hua
Riley Research, Rm. 208, 699 West Indiana University Medical Center, Indianapolis, IN 46202, USA.
Pediatr Res. 2004 Mar;55(3):385-94. doi: 10.1203/01.PDR.0000111482.43827.40. Epub 2004 Jan 7.
Hypoxia preconditioning and subsequent tolerance to hypoxia-ischemia damage is a well-known phenomenon and has significant implications in clinical medicine. In this investigation, we tested the hypothesis that the transcriptional activation of IGF-I is one of the underlying mechanisms for hypoxia-induced neuroprotection. In a rodent model of hypoxia-ischemia, hypoxia preconditioning improved neuronal survival as demonstrated by decreased hypoxia-ischemia-induced neuronal apoptosis. To study the role of IGF-I in hypoxia tolerance, we used in situ hybridization to examine IGF-I mRNA distribution on adjacent tissue sections. In cerebral cortex and hippocampus, hypoxia preconditioning resulted in an increase in neuronal IGF-I mRNA levels with or without hypoxia-ischemia. To test its direct effects, we added IGF-I to primary neuronal culture under varying oxygen concentrations. As oxygen concentration decreased, neuronal survival also decreased, which could be reversed by IGF-I, especially at the lowest oxygen concentration. Interestingly, IGF-I treatment resulted in an activation of hypoxia-inducible factor 1alpha (HIF-1alpha), a master transcription factor for hypoxia-induced metabolic adaptation. To evaluate whether IGF-I transcriptional activation correlates with HIF-1alpha activity, we studied the time course of HIF-1alpha DNA binding activity in the same rat model of hypoxia-ischemia. After hypoxia-ischemia, there was an increase in HIF-1alpha DNA binding activity in cortical tissues, with the highest increase around 24 h. Like IGF-I mRNA levels, hypoxia preconditioning increased HIF-1alpha DNA binding activity alone or with subsequent hypoxia ischemia. Overall, our results suggest that IGF-I transcriptional activation is one of the metabolic adaptive responses to hypoxia, which is likely mediated by a direct activation of HIF-1alpha.
缺氧预处理及随后对缺氧缺血性损伤的耐受性是一种众所周知的现象，在临床医学中具有重要意义。在本研究中，我们检验了以下假设：胰岛素样生长因子-I（IGF-I）的转录激活是缺氧诱导神经保护的潜在机制之一。在缺氧缺血的啮齿动物模型中，缺氧预处理改善了神经元存活，这可通过缺氧缺血诱导的神经元凋亡减少得以证明。为研究IGF-I在缺氧耐受性中的作用，我们使用原位杂交技术检测相邻组织切片上IGF-I mRNA的分布。在大脑皮层和海马体中，无论有无缺氧缺血，缺氧预处理均导致神经元IGF-I mRNA水平升高。为测试其直接作用，我们在不同氧浓度下向原代神经元培养物中添加IGF-I。随着氧浓度降低，神经元存活也减少，而IGF-I可逆转这种情况，尤其是在最低氧浓度时。有趣的是，IGF-I处理导致缺氧诱导因子1α（HIF-1α）激活，HIF-1α是缺氧诱导代谢适应的主要转录因子。为评估IGF-I转录激活是否与HIF-1α活性相关，我们在同一缺氧缺血大鼠模型中研究了HIF-IA DNA结合活性的时间进程。缺氧缺血后，皮层组织中HIF-1α DNA结合活性增加，在约24小时时增加最为明显。与IGF-I mRNA水平一样，缺氧预处理单独或与随后的缺氧缺血一起增加了HIF-1α DNA结合活性。总体而言，我们的结果表明，IGF-I转录激活是对缺氧的代谢适应性反应之一，这可能是由HIF-1α的直接激活介导的。
