Role of moesin in the effect of glucagon-like peptide-1 on advanced glycation end products-induced endothelial barrier dysfunction.
Role of moesin in the effect of glucagon-like peptide-1 on advanced glycation end products-induced endothelial barrier dysfunction.
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DOI：
10.1016/j.cellsig.2021.110193
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发表时间：
2021-11
影响因子：
4.8
通讯作者：
Yan Liu;Zhenzhen Chen;Lei Liu;Haitao Tang;Huaqing Zhu;Songtao Tang
中科院分区：
文献类型：
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作者：
Yan Liu;Zhenzhen Chen;Lei Liu;Haitao Tang;Huaqing Zhu;Songtao Tang
胰高血糖素样肽-1 (GLP-1) 类似物已被发现对血管疾病中的内皮屏障功能障碍发挥保护作用。 Moesin 磷酸化参与晚期糖基化终末产物 (AGE) 诱导的内皮屏障完整性破坏的过程。糖尿病条件下 GLP-1 是否以及如何调节内皮中的 moesin 磷酸化需要进一步阐明。与之前的研究一致，我们的数据表明，体内和体外实验中高血糖和 AGE 促进 EC 中的 moesin 磷酸化。无论有或没有 AGE 孵育，moesin 的过度表达和激活的突变体 moesin T558D 都会增加 EC 的通透性，而 moesin 的敲低则会降低 EC 的通透性。抑制 Rho/ROCK、p38/MAPK 和 PKC β 信号通路也降低了与 AGE 一起孵育的 EC 中的 moesin 磷酸化。重要的是，GLP-1 以剂量依赖性方式抑制 AGE 诱导的 EC 中的 moesin 磷酸化。有趣的是，糖尿病条件下 GLP-1 对 EC 中 moesin 磷酸化的影响会因抑制 cAMP/PKA 和刺激 Rho/ROCK、p38 和 PKC β 信号通路而减弱。因此，本研究证实GLP-1对moesin磷酸化介导的内皮屏障功能的稳定作用是通过GLP-1R/cAMP/PKA激活以及随后下调Rho/ROCK、p38和PKCβ信号通路介导的。
Glucagon-like peptide-1 (GLP-1) analogues have been found to exert protective effect on endothelial barrier dysfunction in vascular diseases. Moesin phosphorylation participates in the process of advanced glycation end products (AGEs) induced disruption of endothelial barrier integrity. Whether and how GLP-1 modulating moesin phosphorylation in endothelium under diabetic condition needs further clarification. Consistent with previous studies, our data showed that hyperglycemia and AGEs promoted moesin phosphorylation in ECs in vivo and vitro experiments. With or without AGEs incubation, overexpression of moesin and activated mutant moesin T558D increased ECs permeability, whereas knockdown of moesin decreased ECs permeability. Inhibition of Rho/ROCK, p38/MAPK and PKC β signal pathways also decreased moesin phosphorylation in ECs incubated with AGEs. Importantly, GLP-1 inhibited moesin phosphorylation in AGE-induced ECs in a dose-dependent manner. Intriguingly, the effects of GLP-1 elicited on moesin phosphorylation in ECs under diabetic condition were blunted by inhibition of cAMP/PKA and stimulation of Rho/ROCK, p38 and PKC β signaling pathways. Therefore, this study verified that the stabilizing effect of GLP-1 on the moesin phosphorylation mediated endothelial barrier function is mediated by GLP-1R/cAMP/PKA activation and subsequent down-regulation of Rho/ROCK, p38 and PKC β signaling pathways.