Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 174, Issue 9, Pages 848-866Publisher
WILEY
DOI: 10.1111/bph.13752
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Funding
- National Natural Science Foundation of China [U1501224, 81370511]
- Natural Science Foundation of Guangdong Province [S2013010016541]
- Science and Technology Planning Projects of Guangzhou City [201604020118, 201604020002]
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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 PGE(2) and its EP4 receptor in the promotion of mucosal proliferation. However, whether -arrestin1 (-arr1), a well-established mediator of GPCRs, is involved in the PGE(2)/EP4 receptor-mediated mucosal proliferation complex in PHG remains unclear. The aim of the study was to investigate whether -arr1 participated in PGE(2)/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 ApproachGastric mucosal proliferation was examined in patients with PHG and the PHG model of -arr1-knockout (-arr1-KO) and -arr1-wild type (-arr1-WT) mice. The induction of -arr1 and EP4 receptor expression and the Src/EGFR signalling elements was investigated, and the mechanisms underlying PGE(2)-regulated gastric mucosal proliferation were analysed. Key ResultsPortal hypertension suppressed COX-1 but not COX-2, which was accompanied by a down-regulation of PGE(2) generation and EP4 receptor levels in the mucosa of patients with PHG. PGE(2) administration markedly promoted mucosal proliferation in a mouse model of PHG. Targeted deletion of -arr1 abolished PGE(2)/EP4 receptor-mediated gastric proliferation in PHG by repressing the Src/EGFR/Akt/PCNA signalling network. Conclusions and ImplicationsThese results indicate that -arr1 regulates PGE(2)/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.
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