可溶性 RAGE 通过破坏 HMGB1 介导的 AT1R 和 RAGE 之间的串扰来减弱 AngII 诱导的内皮高渗透性。,Experimental & Molecular Medicine

当前位置： X-MOL 学术 › Exp. Mol. Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

可溶性 RAGE 通过破坏 HMGB1 介导的 AT1R 和 RAGE 之间的串扰来减弱 AngII 诱导的内皮高渗透性。
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2019-09-27 , DOI: 10.1038/s12276-019-0312-5
Jisu Jeong _{1,

2} , Jiye Lee ₂ , Juyeon Lim _{1,

2} , Soyoung Cho _{1,

2} , Soyoung An ₂ , Myungeun Lee ₂ , Nara Yoon ₃ , Miran Seo ₂ , Soyeon Lim ₄ , Sungha Park _{2,

5}

Affiliation

内皮通透性增加是内皮功能障碍的最早迹象之一，与高血压和动脉粥样硬化等心血管疾病的发展有关。最近的研究表明，晚期糖基化终产物受体 (RAGE) 可调节炎症中的内皮通透性。在本研究中，我们研究了 RAGE 在血管紧张素 II (Ang II)（一种众所周知的炎症介质）诱导的内皮高通透性中的调节机制，以及可溶性 RAGE (sRAGE)（一种 RAGE 配体的诱饵受体）的潜在治疗效果。对于体外研究，用对 RAGE 或 sRAGE 特异的 siRNA 处理 Ang II 处理的人脐静脉内皮细胞 (HUVEC) 以破坏 RAGE 介导的信号传导。使用 FITC 标记的葡聚糖 40 和电阻计估计内皮通透性。为了评估细胞间连接中断，通过蛋白质印迹和免疫细胞化学检查了 VE-钙粘蛋白的表达。Ang II 增加了 Ang II 1 型受体 (AT1R) 和 RAGE 的表达，而这种增加被 sRAGE 抑制。sRAGE 阻止了 HUVEC 中 Ang II 诱导的 VE-钙粘蛋白破坏。对于体内研究，使用了注入 Ang II、易患动脉粥样硬化的载脂蛋白 E 敲除小鼠。通过主动脉的伊文思蓝染色评估内皮通透性。Ang II 增加了内皮屏障通透性，而这种作用被 sRAGE 显着减弱。

"点击查看英文标题和摘要"

Soluble RAGE attenuates AngII-induced endothelial hyperpermeability by disrupting HMGB1-mediated crosstalk between AT1R and RAGE.

Increased endothelial permeability, one of the earliest signs of endothelial dysfunction, is associated with the development of cardiovascular diseases such as hypertension and atherosclerosis. Recent studies suggest that the receptor for advanced glycation end products (RAGE) regulates endothelial permeability in inflammation. In the present study, we investigated the regulatory mechanism of RAGE in endothelial hyperpermeability induced by angiotensin II (Ang II), a well-known inflammatory mediator, and the potential therapeutic effect of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands. For in vitro studies, Ang II-treated human umbilical vein endothelial cells (HUVECs) were treated with siRNA specific to either RAGE or sRAGE to disrupt RAGE-mediated signaling. Endothelial permeability was estimated using FITC-labeled dextran 40 and a resistance meter. To evaluate intercellular junction disruption, VE-cadherin expression was examined by western blotting and immunocytochemistry. Ang II increased the expression of the Ang II type 1 receptor (AT1R) and RAGE, and this increase was inhibited by sRAGE. sRAGE prevented Ang II-induced VE-cadherin disruption in HUVECs. For in vivo studies, Ang II-infused, atherosclerosis-prone apolipoprotein E knockout mice were utilized. Endothelial permeability was assessed by Evans blue staining of the aorta. Ang II increased endothelial barrier permeability, and this effect was significantly attenuated by sRAGE. Our data demonstrate that blockade of RAGE signaling using sRAGE attenuates Ang II-induced endothelial barrier permeability in vitro and in vivo and indicate the therapeutic potential of sRAGE in controlling vascular permeability under pathological conditions.

更新日期：2019-09-27

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文