Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia
Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia
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DOI：
10.1007/s12035-016-0219-2
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发表时间：
2017-11-01
影响因子：
5.1
通讯作者：
Bae, Eun Joo
中科院分区：
文献类型：
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作者：
Lee, Jae-Chul;Tae, Hyun-Jin;Bae, Eun Joo
缺血预处理（IPC）通过特定的机制对随后的严重缺血损伤提供神经保护。我们验证了IPC通过缺氧诱导因子-1 α（HIF-1 α）及其相关因子如血管内皮生长因子（VEGF）和核因子-κ B（NF-κ B）减弱沙土鼠海马CA1区（CA1）缺血后神经元死亡的假设。无IPC的致死性缺血（LI）增加了HIF-1 α、VEGF和p-I κ B-α的表达LI后12 h和/或1 d，CA 1锥体神经元NF-κ B B p65转位入核;此后，随着时间的推移，它们在CA1锥体神经元中的表达逐渐减少，在非锥体细胞中有新的表达（周细胞），和CA 1锥体神经元死亡后5天LI，并在这个时间点，他们的免疫反应性新表达周细胞。IPC/LI组海马CA1区锥体神经元受到良好保护，HIF-1 α、VEGF和p-I κ B-α（/和NF-κ B p65向核内移位）的表达较假手术组显著增加，LI后维持不变。然而，IPC/LI组用2ME 2（一种HIF-1 α抑制剂）处理不能保持IPC介导的HIF-1 α、VEGF和p-I κ B-α表达的增加（/和NF-κ B p65易位到细胞核中），并且没有显示IPC介导的神经保护作用。简而言之，IPC通过上调HIF-1 α、VEGF和p-I κ B-α的表达来保护CA1锥体神经元免受LI。本研究表明，IPC增加海马CA1区锥体神经元中HIF-1 α的表达，从而增强VEGF表达和NF-κ B B活化，IPC可能是脑缺血损伤的治疗干预策略。
Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic insults by specific mechanisms. We tested the hypothesis that IPC attenuates post-ischemic neuronal death in the gerbil hippocampal CA1 region (CA1) throughout hypoxia inducible factor-1 alpha (HIF-1 alpha) and its associated factors such as vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-kappa B). Lethal ischemia (LI) without IPC increased expressions of HIF-1 alpha, VEGF, and p-I kappa B-alpha (/and translocation of NF-kappa B p65 into nucleus) in CA1 pyramidal neurons at 12 h and/or 1-day post-LI; thereafter, their expressions were decreased in the CA1 pyramidal neurons with time and newly expressed in non-pyramidal cells (pericytes), and the CA1 pyramidal neurons were dead at 5-day post-LI, and, at this point in time, their immunoreactivities were newly expressed in pericytes. In animals with IPC subjected to LI (IPC/LI)-group), CA1 pyramidal neurons were well protected, and expressions of HIF-1 alpha, VEGF, and p-I kappa B-alpha (/and translocation of NF-kappa B p65 into nucleus) were significantly increased compared to the sham-group and maintained after LI. Whereas, treatment with 2ME2 (a HIF-1 alpha inhibitor) into the IPC/LI-group did not preserve the IPC-mediated increases of HIF-1 alpha, VEGF, and p-I kappa B-alpha (/and translocation of NF-kappa B p65 into nucleus) expressions and did not show IPC-mediated neuroprotection. In brief, IPC protected CA1 pyramidal neurons from LI by upregulation of HIF-1 alpha, VEGF, and p-I kappa B-alpha expressions. This study suggests that IPC increases HIF-1 alpha expression in CA1 pyramidal neurons, which enhances VEGF expression and NF-kappa B activation and that IPC may be a strategy for a therapeutic intervention of cerebral ischemic injury.