Overexpression of sFlt-1 represses ox-LDL-induced injury of HUVECs by activating autophagy via PI3K/AKT/mTOR pathway
Overexpression of sFlt-1 represses ox-LDL-induced injury of HUVECs by activating autophagy via PI3K/AKT/mTOR pathway
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DOI：
10.1016/j.mvr.2021.104252
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发表时间：
2021-09-16
影响因子：
3.1
通讯作者：
Wang, Wei
中科院分区：
文献类型：
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作者：
Zhou, Yi-Hua;Tang, Yu-Zhi;Wang, Wei
可溶性fms样酪氨酸激酶-1 （sFlt-1）是一种循环抗血管生成蛋白，参与动脉粥样硬化（AS）的发病机制，其潜在机制尚不清楚。在这里，我们试图探讨sFlt-1在AS中的作用机制。用氧化低密度脂蛋白（ox-LDL）处理人脐静脉内皮细胞（HUVECs），诱导细胞损伤。ox-LDL处理增加HUVECs中LC3-II/LC3-I比值、Beclin-1表达和GFP-LC3点，提示ox-LDL可能诱导HUVECs自噬通量损伤。ox- ldl处理的HUVECs显示sFlt-1水平降低。此外，ox-LDL处理可降低HUVECs的细胞增殖并升高凋亡，这一作用被sFlt-1过表达所消除。在ox-LDL处理后，sFlt-1的上调抑制了PI3K/AKT/mTOR信号通路的活性，增强了HUVECs的自噬。此外，在ox- ldl处理的HUVECs中，sFlt-1过表达介导的自噬增加被3-甲基腺嘌呤（自噬抑制剂）所消除。3-甲基腺嘌呤消除了sFlt-1过表达对ox- ldl处理HUVECs增殖和凋亡的影响。本研究证实sFlt-1过表达通过抑制PI3K/Akt/mTOR信号通路激活自噬，从而减轻ox- ldl诱导的HUVECs损伤。因此，本研究提示sFlt-1可能是治疗AS的潜在靶点。
Soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antiangiogenic protein, is involved in the pathogenesis of atherosclerosis (AS), and the underlying mechanism is still unclear. Here, we attempted to investigate the mechanism of action of sFlt-1 in AS. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized low density lipoprotein (ox-LDL) to induce cell injury. ox-LDL treatment increased LC3-II/LC3-I ratio, Beclin-1 expression and GFP-LC3 puncta in HUVECs, suggesting that ox-LDL may induce autophagic flux impairment in HUVECs. ox-LDL-treated HUVECs displayed a decrease of sFlt-1 levels. Moreover, ox-LDL treatment reduced cell proliferation and elevated apoptosis in HUVECs, which was abrogated by sFlt-1 overexpression. Up-regulation of sFlt-1 repressed the activity of PI3K/AKT/mTOR signaling pathway and enhanced autophagy in HUVECs following ox-LDL treatment. Additionally, sFlt-1 overexpression-mediated increase of autophagy in ox-LDL-treated HUVECs was abolished by 3-methyladenine (autophagy inhibitor). 3-methyladenine abrogated the impact of sFlt-1 overexpression on proliferation and apoptosis in ox-LDL-treated HUVECs. This work confirmed that overexpression of sFlt-1 activated autophagy by repressing PI3K/Akt/mTOR signaling pathway, and thus alleviated ox-LDL-induced injury of HUVECs. Therefore, this study suggests that sFlt-1 may be a potential target for AS treatment.