载脂蛋白 L2 通过调控 HMGB1/Nrf2/HO-1 通路促进内皮细胞铁死亡加重静脉溶栓后血脑屏障功能障碍。
Lipocalin-2 aggravates blood-brain barrier dysfunction after intravenous thrombolysis by promoting endothelial cell ferroptosis via regulating the HMGB1/Nrf2/HO-1 pathway.
机构信息
Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, China.
Stroke Center, Department of Neurology, The First Hospital of Jilin University, Chang Chun, China; Neuroscience Research Center, Department of Neurology, First Hospital of Jilin University, Chang Chun, China.
出版信息
Redox Biol. 2024 Oct;76:103342. doi: 10.1016/j.redox.2024.103342. Epub 2024 Sep 5.
BACKGROUND
Disruption of the blood-brain barrier (BBB) is a major contributor to hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) following intravenous thrombolysis (IVT). However, the clinical therapies aimed at BBB protection after IVT remain limited.
METHODS
One hundred patients with AIS who underwent IVT were enrolled (42 with HT and 58 without HT 24 h after IVT). Based on the cytokine chip, the serum levels of several AIS-related proteins, including LCN2, ferritin, matrix metalloproteinase-3, vascular endothelial-derived growth factor, and X-linked inhibitor of apoptosis, were detected upon admission, and their associations with HT were analyzed. After finding that LCN2 was related to HT in patients with IVT, we clarified whether the modulation of LCN2 influenced BBB dysfunction and HT after thrombolysis and investigated the potential mechanism.
RESULTS
In patients with AIS following IVT, logistic regression analysis showed that baseline serum LCN2 (p = 0.023) and ferritin (p = 0.046) levels were independently associated with HT. A positive correlation between serum LCN2 and ferritin levels was identified in patients with HT. In experimental studies, recombinant LCN2 (rLCN2) significantly aggravated BBB dysfunction and HT in the thromboembolic stroke rats after thrombolysis, whereas LCN2 inhibition by ZINC006440089 exerted opposite effects. Further mechanistic studies showed that, LCN2 promoted endothelial cell ferroptosis, accompanied by the induction of high mobility group box 1 (HMGB1) and the inhibition of nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Ferroptosis inhibitor ferrostatin-1 (fer-1) significantly restricted the LCN2-mediated BBB disruption. Transfection of LCN2 and HMGB1 siRNA inhibited the endothelial cell ferroptosis, and this effects was reversed by Nrf2 siRNA.
CONCLUSION
LCN2 aggravated BBB disruption after thrombolysis by promoting endothelial cell ferroptosis via regulating the HMGB1/Nrf2/HO-1 pathway, this may provide a promising therapeutic target for the prevention of HT after IVT.
背景
血脑屏障（BBB）的破坏是急性缺血性脑卒中（AIS）患者静脉溶栓（IVT）后发生出血性转化（HT）的主要原因。然而，针对 IVT 后 BBB 保护的临床治疗方法仍然有限。
方法
纳入 100 例接受 IVT 的 AIS 患者（42 例发生 HT，58 例 IVT 后 24 小时无 HT）。根据细胞因子芯片，检测入院时与 AIS 相关的几种蛋白质（包括 LCN2、铁蛋白、基质金属蛋白酶-3、血管内皮衍生生长因子和 X 连锁凋亡抑制剂）的血清水平，并分析它们与 HT 的关系。发现 LCN2 与 IVT 患者的 HT 相关后，我们明确了 LCN2 的调节是否会影响溶栓后的 BBB 功能障碍和 HT，并探讨了潜在的机制。
结果
在接受 IVT 的 AIS 患者中，逻辑回归分析显示，基线血清 LCN2（p=0.023）和铁蛋白（p=0.046）水平与 HT 独立相关。HT 患者血清 LCN2 和铁蛋白水平呈正相关。在实验研究中，重组 LCN2（rLCN2）显著加重了溶栓后血栓栓塞性脑卒中大鼠的 BBB 功能障碍和 HT，而 LCN2 抑制剂 ZINC006440089 则产生了相反的效果。进一步的机制研究表明，LCN2 促进内皮细胞铁死亡，同时诱导高迁移率族蛋白 1（HMGB1），并抑制核转录因子 E2 相关因子 2（Nrf2）和血红素加氧酶-1（HO-1）蛋白的核转位。铁死亡抑制剂 ferrostatin-1（fer-1）显著限制了 LCN2 介导的 BBB 破坏。转染 LCN2 和 HMGB1 siRNA 抑制了内皮细胞铁死亡，而 Nrf2 siRNA 逆转了这一作用。
结论
LCN2 通过调节 HMGB1/Nrf2/HO-1 通路促进内皮细胞铁死亡，从而加重溶栓后 BBB 破坏，这可能为预防 IVT 后 HT 提供有希望的治疗靶点。
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