PGE2 /EP4 receptor attenuated mucosal injury via β-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy.

Siwei Tan, Xiaoliang Chen, Minyi Xu, Xiaoli Huang, Huiling Liu, Jie Jiang, Yu Lu, Xiaojie Peng, Bin Wu

British journal of pharmacology 2017 May

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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. 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. 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. 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. © 2017 The British Pharmacological Society.

Citation

Siwei Tan, Xiaoliang Chen, Minyi Xu, Xiaoli Huang, Huiling Liu, Jie Jiang, Yu Lu, Xiaojie Peng, Bin Wu. PGE2 /EP4 receptor attenuated mucosal injury via β-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy. British journal of pharmacology. 2017 May;174(9):848-866