PGE(2)/EP4 receptor attenuated mucosal injury via beta-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy
PGE(2)/EP4 receptor attenuated mucosal injury via beta-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy
复制标题
PGE(2)/EP4受体通过β-arrestin1/Src/EGFR介导的增殖减轻门静脉高压性胃病的粘膜损伤
DOI：
10.1111/bph.13752
复制
发表时间：
2017
影响因子：
7.3
通讯作者：
Wu Bin
中科院分区：
文献类型：
--
作者：
Tan Siwei;Chen Xiaoliang;Xu Minyi;Huang Xiaoli;Liu Huiling;Jiang Jie;Lu Yu;Peng Xiaojie;Wu Bin
背景和目的门脉高压性胃病（PHG）是肝硬化的严重并发症，也是肝硬化患者出血的潜在原因。粘膜上皮细胞增殖抑制是PHG的重要病理特征。我们的研究表明PGE 2及其EP 4受体在促进粘膜增殖中起重要作用。然而，β-arrestin 1（β-arr 1），一种公认的GPCR介导剂，是否参与PHG中PGE 2/EP 4受体介导的粘膜增殖复合物仍不清楚。本研究的目的是研究β-arr 1是否通过募集Src/EGF受体（EGFR）复合物来激活PHG.Experimental Approach中Akt/增殖细胞核抗原（PCNA）信号传导参与PGE 2/EP 4受体介导的粘膜增殖。在PHG患者和β-arr 1-敲除（β-arr 1-KO）和β-arr 1-野生型（β-arr 1-WT）小鼠PHG模型中检查胃粘膜增殖。研究了β-arr 1和EP 4受体表达和Src/EGFR信号传导元件的诱导，并分析了PGE 2调节胃粘膜增殖的潜在机制。Key ResultsPortalhypertension抑制考克斯-1，但不抑制考克斯-2，这伴随着PHG患者粘膜中PGE 2生成和EP 4受体水平的下调。在PHG小鼠模型中，给予PGE 2显著促进粘膜增殖。靶向缺失β-arr 1可通过抑制Src/EGFR/Akt/PCNA信号通路，抑制PGE 2/EP 4受体介导的PHG胃黏膜增殖，提示β-arr 1通过促进Src/EGFR/Akt/PCNA信号通路的激活，调控PGE 2/EP 4受体介导的胃黏膜增殖，因此，该信号通路是PHG潜在的治疗靶点。
Background and PurposePortal hypertensive gastropathy (PHG) is a serious complication of liver cirrhosis and a potential cause of bleeding in patients with cirrhosis. Suppressed mucosal epithelial proliferation is a crucial pathological characteristic of PHG. Our studies demonstrated an important role for PGE2and its EP4receptor in the promotion of mucosal proliferation. However, whether β‐arrestin1 (β‐arr1), a well‐established mediator of GPCRs, is involved in the PGE2/EP4receptor‐mediated mucosal proliferation complex in PHG remains unclear. The aim of the study was to investigate whether β‐arr1 participated in PGE2/EP4receptor‐mediated mucosal proliferation by recruiting the Src/EGF receptor (EGFR) complex to activate Akt/proliferating cell nuclear antigen (PCNA) signalling in PHG.Experimental ApproachGastric mucosal proliferation was examined in patients with PHG and the PHG model ofβ‐arr1‐knockout (β‐arr1‐KO) andβ‐arr1‐wild type (β‐arr1‐WT) mice. The induction of β‐arr1 and EP4receptor expression and the Src/EGFR signalling elements was investigated, and the mechanisms underlying PGE2‐regulated gastric mucosal proliferation were analysed.Key ResultsPortal hypertension suppressed COX‐1 but not COX‐2, which was accompanied by a down‐regulation of PGE2generation and EP4receptor levels in the mucosa of patients with PHG. PGE2administration markedly promoted mucosal proliferation in a mouse model of PHG. Targeted deletion ofβ‐arr1abolished PGE2/EP4receptor‐mediated gastric proliferation in PHG by repressing the Src/EGFR/Akt/PCNA signalling network.Conclusions and ImplicationsThese results indicate that β‐arr1 regulates PGE2/EP4receptor‐mediated mucosal proliferation by promoting activation of the Src/EGFR/Akt/PCNA signalling pathway, and thus, this network is a potential therapeutic target for PHG.