Non-Lethal Doses of RSL3 Impair Microvascular Endothelial Barrier through Degradation of Sphingosie-1-Phosphate Receptor 1 and Cytoskeletal Arrangement in A Ferroptosis-Independent Manner.
Non-Lethal Doses of RSL3 Impair Microvascular Endothelial Barrier through Degradation of Sphingosie-1-Phosphate Receptor 1 and Cytoskeletal Arrangement in A Ferroptosis-Independent Manner.
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DOI：
10.3390/biomedicines11092451
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发表时间：
2023-09-04
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
微血管内皮通透性过度是急性炎症性疾病的标志。维持微血管的完整性是防止血管成分渗漏到周围组织的关键。鞘氨醇-1-磷酸（S1P）是一种活性溶血磷脂，通过激活其受体S1PR1增强内皮细胞（EC）屏障。在这里，我们描述了非致死剂量的RSL3（谷胱甘肽过氧化物酶4 （GPX4）抑制剂）对EC屏障功能的影响。低剂量RSL3 （50-100 nM）可减弱s1p诱导的人肺微血管屏障增强和AKT磷酸化。为了研究RSL3减弱S1P作用的分子机制，我们检测了S1PR1的水平。RSL3处理在1小时内降低了S1PR1水平，而蛋白酶体和溶酶体抑制剂以及脂质筏抑制剂的作用减弱。免疫荧光染色显示RSL3诱导S1PR1从质膜内化到细胞质。此外，我们发现RSL3 （100 nM和200 nM）在不改变细胞活力的情况下增加了EC屏障通透性和细胞骨架重排。综上所述，我们的数据描述了非致死剂量的RSL3通过两种机制损害EC屏障功能。RSL3减弱s1p1诱导的EC屏障增强，并通过生成4-羟基壬烯（4HNE）破坏EC屏障的完整性。所有这些影响都与铁下垂无关。
The excess microvascular endothelial permeability is a hallmark of acute inflammatory diseases. Maintenance of microvascular integrity is critical to preventing leakage of vascular components into the surrounding tissues. Sphingosine-1-phosphate (S1P) is an active lysophospholipid that enhances the endothelial cell (EC) barrier via activation of its receptor S1PR1. Here, we delineate the effect of non-lethal doses of RSL3, an inhibitor of glutathione peroxidase 4 (GPX4), on EC barrier function. Low doses of RSL3 (50–100 nM) attenuated S1P-induced human lung microvascular barrier enhancement and the phosphorylation of AKT. To investigate the molecular mechanisms by which RSL3 attenuates S1P’s effect, we examined the S1PR1 levels. RSL3 treatment reduced S1PR1 levels in 1 h, whereas the effect was attenuated by the proteasome and lysosome inhibitors as well as a lipid raft inhibitor. Immunofluorescence staining showed that RSL3 induced S1PR1 internalization from the plasma membrane into the cytoplasm. Furthermore, we found that RSL3 (100 and 200 nM) increased EC barrier permeability and cytoskeletal rearrangement without altering cell viability. Taken together, our data delineates that non-lethal doses of RSL3 impair EC barrier function via two mechanisms. RSL3 attenuates S1P1-induced EC barrier enhancement and disrupts EC barrier integrity through the generation of 4-hydroxynonena (4HNE). All these effects are independent of ferroptosis.
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影响因子：
4.6
作者：
Cai J;Wei J;Li S;Suber T;Zhao J
通讯作者：
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影响因子：
7.8
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影响因子：
3.3
作者：
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在炎症诱导的急性肺损伤中，P38/MAPK 通过 MAP4 磷酸化依赖性微管解体导致内皮屏障功能障碍。
影响因子：
4.6
作者：
Li L;Hu J;He T;Zhang Q;Yang X;Lan X;Zhang D;Mei H;Chen B;Huang Y
通讯作者：
Huang Y
DOI：
10.1152/ajplung.00372.2003
发表时间：
2004-11-01
影响因子：
4.9
作者：
Borbiev, T;Birukova, A;Verin, AD
通讯作者：
Verin, AD