GAS6/Axl Signaling Modulates Blood-Brain Barrier Function Following Intravenous Thrombolysis in Acute Ischemic Stroke.
GAS6/Axl Signaling Modulates Blood-Brain Barrier Function Following Intravenous Thrombolysis in Acute Ischemic Stroke.
复制标题
GAS6/Axl 信号传导调节急性缺血性中风静脉溶栓后的血脑屏障功能
DOI：
10.3389/fimmu.2021.742359
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发表时间：
2021
影响因子：
7.3
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Guo ZN;Liu J;Chang J;Zhang P;Jin H;Sun X;Yang Y
背景与目的近年来的研究表明，包括Axl在内的几种蛋白质通过影响血脑屏障（BBB）功能与静脉溶栓后的出血性转化（HT）有关。然而，这些蛋白质对BBB功能的影响主要是在动物模型中研究的。在这项研究中，我们的目的是确定血清蛋白标志物，预测HT静脉溶栓治疗急性缺血性卒中（AIS）患者，并验证这些血清蛋白是否调节BBB功能和HT在动物中风模型。方法首先，118例AIS患者纳入本研究，其中HT患者52例，非HT患者66例。在步骤1中，使用定量细胞因子芯片测量Axl、血管生成素样4、C反应蛋白、铁蛋白、缺氧诱导因子-1 α、HTRA 2、脂质运载蛋白2、基质金属肽酶9、血小板衍生生长因子-BB和肿瘤坏死因子α的基线血清水平。接下来，检测编码步骤1中鉴定的差异表达蛋白质和随后的功能相关蛋白质的基因的序列突变和变异。最后，我们验证了差异表达蛋白的操作是否影响血脑屏障功能和HT在高血糖诱导的大鼠中风模型。结果HT组血清Axl水平显著低于非HT组，其他蛋白质指标两组间无显著性差异。基因检测显示，GAS 6（编码Axl配体的基因）衍生的长非编码RNA（GAS 6-AS 1）的序列变异与静脉溶栓后HT风险增加显著相关。在动物研究中，给予重组GAS 6显著减少脑梗死和神经功能缺损，并减弱BBB破坏和HT。结论GAS 6-AS 1基因序列变异导致的Axl水平降低与脑卒中患者静脉溶栓后HT风险增加相关。通过GAS 6蛋白激活Axl信号传导途径可以作为减少AIS患者HT的治疗策略。
Background and Purpose Recent studies have shown that several proteins, including Axl, are related to hemorrhagic transformation (HT) following intravenous thrombolysis by affecting blood-brain barrier (BBB) function. However, the effects of these proteins on BBB function have been studied primarily in animal models. In this study, we aimed to identify serum protein markers that predict HT following intravenous thrombolysis in patients with acute ischemic stroke (AIS) and verify whether these serum proteins regulate BBB function and HT in animal stroke models. Methods First, 118 AIS patients were enrolled in this study, including 52 HT patients and 66 non-HT patients. In Step 1, baseline serum levels of Axl, angiopoietin-like 4, C-reactive protein, ferritin, hypoxia-inducible factor-1 alpha, HTRA2, Lipocalin2, matrix metallopeptidase 9, platelet-derived growth factor-BB, and tumor necrosis factor alpha were measured using a quantitative cytokine chip. Next, sequence mutations and variations in genes encoding the differentially expressed proteins identified in Step 1 and subsequent function-related proteins were detected. Finally, we verified whether manipulation of differentially expressed proteins affected BBB function and HT in a hyperglycemia-induced rat stroke model. Results Serum Axl levels were significantly lower in the HT group than in the non-HT group; none of the other protein markers differed significantly between the two groups. Genetic testing revealed that sequence variations of GAS6 (the gene encoding the Axl ligand)-derived long non-coding RNA, GAS6-AS1, were significantly correlated with an increased risk of HT after intravenous thrombolysis. In animal studies, administration of recombinant GAS6 significantly reduced brain infarction and neurological deficits and attenuated BBB disruption and HT. Conclusions Lower serum Axl levels, which may result from sequence variations in GAS6-AS1, are correlated with an increased risk of HT after intravenous thrombolysis in stroke patients. Activation of the Axl signaling pathway by the GAS6 protein may serve as a therapeutic strategy to reduce HT in AIS patients.
影响因子：
2.9
作者：
Soejima Y;Ostrowski RP;Manaenko A;Fujii M;Tang J;Zhang JH
通讯作者：
Zhang JH