title: PGE2/EP4receptor attenuated mucosal injury via β-arrestin1/Src/EGFR-mediated proliferation in portal hypertensive gastropathy.
abstract: 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 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.
  
  
  
  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 EP4receptor 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 PGE2generation and EP4receptor levels in the mucosa of patients with PHG. PGE2administration markedly promoted mucosal proliferation in a mouse model of PHG. Targeted deletion of β-arr1 abolished PGE2/EP4receptor-mediated gastric proliferation in PHG by repressing the Src/EGFR/Akt/PCNA signalling network.
  
  
  
  These 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.
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Siwei
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Minyi
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.|Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D015232:Dinoprostone / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000502:physiology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology*; D000071559:beta-Arrestin 1 / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: C000605255:Arrb1 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000071559:beta-Arrestin 1; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D015232:Dinoprostone