Dataset Information
PGE2 /EP4 receptor attenuated mucosal injury via β-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy.
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ABSTRACT: 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.
SUBMITTER: Tan S
PROVIDER: S-EPMC5386997 | biostudies-literature | 2017 May
REPOSITORIES: biostudies-literature
Publications
PGE<sub>2</sub> /EP<sub>4</sub> receptor attenuated mucosal injury via β-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy.
British journal of pharmacology 20170325 9
<h4>Background and purpose</h4>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 PGE<sub>2</sub> and its EP<sub>4</sub> receptor in the promotion of mucosal proliferation. However, whether β-arrestin1 (β-arr1), a well-established mediator of GPCRs, is involved in t ...[more]