Urocortin increased LPS‐induced endothelial permeability by regulating the cadherin–catenin complex via corticotrophin‐releasing hormone receptor 2
Urocortin increased LPS‐induced endothelial permeability by regulating the cadherin–catenin complex via corticotrophin‐releasing hormone receptor 2
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DOI：
10.1002/jcp.24286
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发表时间：
2013-06
影响因子：
5.6
通讯作者：
Rong Wan;Rui Guo;Cheng Chen;Lai Jin;Chao Zhu;Qichun Zhang;Youhua Xu;Shengnan Li
中科院分区：
文献类型：
--
作者：
Rong Wan;Rui Guo;Cheng Chen;Lai Jin;Chao Zhu;Qichun Zhang;Youhua Xu;Shengnan Li
尿皮质素（Ucn1）是促肾上腺皮质激素释放激素（CRH）家族的一员，据报道在炎症性疾病中上调，并作为自分泌或旁分泌炎症介质发挥作用。越来越多的证据表明，Ucn1增加炎症条件下内皮细胞的通透性；然而，具体机制尚不清楚。在本研究中，我们研究了Ucn1在暴露于脂多糖（LPS）的人脐静脉内皮细胞（HUVECs）中增加内皮通透性的机制。用Ucn1预处理HUVECs可增加内皮细胞的通透性，LPS可协同增强内皮细胞的通透性。VE‐cadherin的表达也显著下调。此外，Ucn1以时间和CRHR2依赖的方式增加了蛋白激酶D （PKD）和热休克蛋白27 （HSP27）的磷酸化。抑制PKD和HSP27可显著减弱Ucn1诱导的VE - cadherin表达下调。进一步的研究表明，Ucn1磷酸化β - catenin的Ser552位点，破坏cadherin - catenin复合物，从而促进β - catenin和VE - cadherin的分离。β - catenin和VE - cadherin的分离导致VE - cadherin的表达降低，而β - catenin的表达升高，这可能是由于GSK - 3β的失活所致。增加的β -连环蛋白易位到细胞核，随后结合到TCF/LEF位点，导致血管内皮生长因子（VEGF）的表达升高。CRHR2受体阻断剂antisauvagine‐30完全逆转了Ucn1的上述作用。综上所述，我们的数据表明，Ucn1通过激活CRHR2和PKD - HSP27信号通路，破坏VE - cadherin -β - catenin复合物，从而增加LPS诱导的内皮通透性。j .细胞。中国生物医学工程学报，2016,33(2):559 - 563。©2012 Wiley期刊公司
Urocortin (Ucn1), a member of corticotrophin‐releasing hormone (CRH) family, has been reported to be upregulated in inflammatory diseases and function as an autocrine or paracrine inflammatory mediator. Growing evidence shows that Ucn1 increases the endothelial permeability in inflammatory conditions; however, the detailed mechanisms are not clear. In the present study, we investigated the mechanisms of increased endothelial permeability by Ucn1 in human umbilical vein endothelial cells (HUVECs) exposed to lipopolysaccharide (LPS). Pretreatment of HUVECs with Ucn1 increased the endothelial cell permeability, which was augmented by LPS synergistically. Significant downregulation of VE‐cadherin expression was also observed. Moreover, Ucn1 increased phosphorylation of protein kinase D (PKD) and heat shock protein 27 (HSP27) in a time‐ and CRHR2‐dependent manner. Inhibition of PKD and HSP27 drastically attenuated Ucn1‐induced downregulation of VE‐cadherin expression. Further investigations demonstrated that Ucn1 phosphorylated β‐catenin at Ser552 to disrupt the cadherin–catenin complex and hence promote the disassociation of β‐catenin and VE‐cadherin. Disassociation of β‐catenin and VE‐cadherin resulted in decreased VE‐cadherin expression while on the contrary β‐catenin was increased, which may due to the inactivation of GSK‐3β. Increased β‐catenin translocated into the nucleus and subsequently bound to TCF/LEF site, contributing to the elevated expression of vascular endothelial growth factor (VEGF). The above effects of Ucn1 were completely reversed by CRHR2 receptor blocker, antisauvagine‐30. Taken together, our data suggest that Ucn1 increase LPS‐induced endothelial permeability by disrupting the VE‐cadherin–β‐catenin complex via activation of CRHR2 and PKD‐HSP27 signaling pathway. J. Cell. Physiol. 228: 1295–1303, 2013. © 2012 Wiley Periodicals, Inc.