Laboratory of Molecular Iron Metabolism, Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, Hebei Province, China.
Neuromedical Technology Innovation Center of Hebei Province, Brain Aging and Cognitive Neuroscience Laboratory of Hebei Province, Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei Province, China.
Cell Death Dis. 2023 Feb 25;14(2):161. doi: 10.1038/s41419-023-05688-1.
Ischemic stroke is associated with high mortality and morbidity rates worldwide. However, the molecular mechanisms underlying the neuronal damage incurred by stroke victims remain unclear. It has previously been reported that ischemic stroke can induce an increase in the levels of brain iron, which is an important factor of in the associated brain damage. Ferroportin 1 (FPN1), the only known cellular iron export protein, is found in brain microvascular endothelial cells (BMVECs) at the blood-brain barrier, and is considered the gateway for entry of plasma iron into the central nervous system. Despite the connection of brain iron to neuronal damage, the role of BMVECs FPN1 in ischemic stroke remains unexplored. Herein, we conditionally deleted Fpn1 in mouse endothelial cells (ECs), using VE-cadherin-Cre transgenic mice, and explored the impact on brain iron homeostasis after stroke. Our data demonstrated that Fpn1 knockout in ECs decreased the brain iron levels in mice, attenuated the oxidative stress and inflammatory responses after stroke, and inhibited both ferroptosis and apoptosis, ultimately alleviating neurological impairment and decreasing cerebral infarct volume during the acute phase of ischemic stroke. By contrast, we found that Fpn1 knockout in ECs delayed the recovery of neurological function in mice following ischemic stroke. We also found that ECs Fpn1 knockout decreased the brain iron levels after stroke, exacerbated glial cell proliferation, and inhibited neuronal development, indicating that the diminished brain iron levels hindered the repair of neural injury in mice. In conclusion, our findings reveal a dual consequence of FPN1 deficiency in ECs in the development of ischemic stroke. More specifically, iron deficiency initially exerts a neuroprotective effect during the acute phase of ischemic stroke but inhibits recovery during the later stages. Our findings are important to the development of iron- or FPN1-targeting therapeutics for the treatment of ischemic stroke.
缺血性中风在全球范围内与高死亡率和发病率有关。然而，中风患者神经元损伤的分子机制尚不清楚。先前有报道称，缺血性中风可导致脑铁水平升高，这是相关脑损伤的一个重要因素。铁蛋白 1 (FPN1) 是唯一已知的细胞铁输出蛋白，存在于血脑屏障中的脑微血管内皮细胞 (BMVECs) 中，被认为是血浆铁进入中枢神经系统的门户。尽管脑铁与神经元损伤有关，但 BMVECs FPN1 在缺血性中风中的作用仍未被探索。在此，我们使用 VE-cadherin-Cre 转基因小鼠条件性敲除了小鼠内皮细胞 (ECs) 中的 Fpn1，并探讨了其对中风后脑铁稳态的影响。我们的数据表明，ECs 中的 Fpn1 敲除可降低小鼠脑铁水平，减轻中风后的氧化应激和炎症反应，抑制铁死亡和细胞凋亡，从而在缺血性中风的急性期减轻神经损伤和减少脑梗死体积。相比之下，我们发现 ECs 中的 Fpn1 敲除会延迟中风后小鼠神经功能的恢复。我们还发现，ECs 中的 Fpn1 敲除可降低中风后小鼠的脑铁水平，加剧神经胶质细胞增殖，并抑制神经元发育，表明脑铁水平降低会阻碍小鼠神经损伤的修复。总之，我们的研究结果揭示了 ECs 中 FPN1 缺失在缺血性中风发展中的双重后果。具体来说，缺铁在缺血性中风的急性期最初发挥神经保护作用，但在后期阶段抑制恢复。我们的研究结果对于开发针对缺血性中风的铁或 FPN1 靶向治疗具有重要意义。
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