Article date: May 2017
By: Siwei Tan, Xiaoliang Chen, Minyi Xu, Xiaoli Huang, Huiling Liu, Jie Jiang, Yu Lu, Xiaojie Peng, Bin Wu in Volume 174, Issue 9, pages 848-866
Background and Purpose
Portal 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 PGE2 and its EP4 receptor in the promotion of mucosal proliferation. However, whether β‐arrestin1 (β‐arr1), a well‐established mediator of GPCRs, is involved in the PGE2/EP4 receptor‐mediated mucosal proliferation complex in PHG remains unclear. The aim of the study was to investigate whether β‐arr1 participated in PGE2/EP4 receptor‐mediated mucosal proliferation by recruiting the Src/EGF receptor (EGFR) complex to activate Akt/proliferating cell nuclear antigen (PCNA) signalling in PHG.
Experimental Approach
Gastric mucosal proliferation was examined in patients with PHG and the PHG model of β‐arr1‐knockout (β‐arr1‐KO) and β‐arr1‐wild type (β‐arr1‐WT) mice. The induction of β‐arr1 and EP4 receptor expression and the Src/EGFR signalling elements was investigated, and the mechanisms underlying PGE2‐regulated gastric mucosal proliferation were analysed.
Key Results
Portal hypertension suppressed COX‐1 but not COX‐2, which was accompanied by a down‐regulation of PGE2 generation and EP4 receptor levels in the mucosa of patients with PHG. PGE2 administration markedly promoted mucosal proliferation in a mouse model of PHG. Targeted deletion of β‐arr1 abolished PGE2/EP4 receptor‐mediated gastric proliferation in PHG by repressing the Src/EGFR/Akt/PCNA signalling network.
Conclusions and Implications
These results indicate that β‐arr1 regulates PGE2/EP4 receptor‐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.
DOI: 10.1111/bph.13752
View this article