Peptide5 Attenuates rtPA Related Brain Microvascular Endothelial Cells Reperfusion Injury via the Wnt/β-Catenin Signalling Pathway
Peptide5 Attenuates rtPA Related Brain Microvascular Endothelial Cells Reperfusion Injury via the Wnt/β-Catenin Signalling Pathway
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DOI：
10.2174/1567202618666210809115305
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发表时间：
2021-01-01
影响因子：
2.1
通讯作者：
Yang, Xiaobo
中科院分区：
文献类型：
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作者：
Ren, Weimin;Huang, Chuyi;Yang, Xiaobo
目的：rtPA治疗后脑血管内皮细胞功能障碍是预后不良的重要因素，提示缓解rtPA相关的内皮细胞损伤可能是与rtPA溶栓一起的潜在有益策略。背景：重组组织型纤溶酶原激活剂（rtPA）溶栓对急性缺血性脑卒中是有益的，但可能增加出血转化（HT）的风险，这被认为是缺血再灌注损伤。其潜在原因可能与rtPA抗缺血性卒中相关的脑内皮损伤和功能障碍有关。先前的研究表明，在视网膜缺血时使用肽5 （Cx43模拟肽）短暂阻断Cx43可减少血管渗漏，因此有必要了解这是否有助于在治疗时间窗内减少rtPA的副作用。目的：本研究旨在探讨肽5在治疗时间窗内对rtpa相关的缺氧/再氧化（H/R）细胞损伤的影响。方法：建立培养的大鼠脑微血管内皮细胞（RBMECs）细胞缺氧/复氧H/R模型，评价rtPA加或不加瞬时肽5处理后内皮细胞的死亡和通透性。此外，我们还研究了潜在的信号通路，初步探讨其潜在机制。结果：肽5抑制rtpa相关内皮细胞的死亡和通透性。它还略微增加了紧密连接（ZO-1, occluding, claudin-5）和β -catenin mRNA的表达，表明肽5可能通过调节Wnt/ β -catenin通路来减轻内皮细胞损伤。随后对GEO数据集GSE37239的生物信息学探索也与我们的发现一致。结论：本研究表明，肽5的应用维持了rtPA治疗相关的细胞活力和通透性，揭示了一种可能的途径，可以用来限制缺血性卒中时rtPA相关的内皮细胞损伤。此外，Wnt/ β catenin信号通路的改变表明，与Cx43相关的信号通路在未来可能具有潜在的应用价值。本研究可为减轻HT及辅助rtPA在缺血性脑卒中中的应用提供新的途径。
Aims: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. Background: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of Hemorrhagic Transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. Objective: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. Methods: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary Rat Brain Microvascular Endothelial Cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. Results: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and beta-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/beta-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. Conclusion: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/beta catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.