Dataset Information

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

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 |

REPOSITORIES: biostudies-literature

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Project description:To investigates the mucoprotective effect of genistein on gastric injury in rats with indomethacin (IMN)-induced gastropathy.Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control; n = 6) was given distilled water (DW). Group 2 (IMN; n = 6) was given indomethacin (IMN) 150 mg/kg dissolved in 5% sodium bicarbonate (NaHCO3-) 1 mL/rat via intragastric tube at time 0 and 4 h. Group 3 (genistein; n = 6) was given genistein 100 mg/kg dissolved in 0.1% dimethyl sulfoxide (DMSO) plus IMN 150 mg/kg at time described as group 2. Four hours after the second dose, the stomach was removed to examine iNOS western blot expression, malondialdehyde (MDA), and histopathologic examination. Serum was collected to determine TNF-alpha and prostaglandin E2 (PGE2) levels using ELISA technique.Tissue MDA and serum TNF-alpha were significantly increased in the IMN group, as compared to the control group (9.70 ± 0.40 vs. 1.56 ± 0.14 nmol/mg protein, P = 0.000; 210.28 ± 0.98 vs. 126.4 ± 0.13 pg/mL, P = 0.000, respectively) and decreased in the genistein group when compared to the IMN group (2.87 ± 0.37 vs. 9.70 ± 0.40 nmol/mg protein, P = 0.000; 156.59 ± 0.10 vs. 210.28 ± 0.98 pg/mL, P = 0.000, respectively). Serum PGE2 level in IMN group was decreased significantly compared with control group (152.83 ± 0.10 vs. 303.33 ± 2.16 pg/mL, P = 0.000) and increased in the genistein group compared to the IMN group (247.65 ± 0.01 vs. 152.83 ± 0.10 pg/mL, P = 0.000). Expression of tissue iNOS was increased in the IMN group and improved in genistein groups. Most of the rats in the IMN group developed moderate to severe gastric erosion and ulcers. Gastric erosions and neutrophil infiltration score were significantly decreased in the genistein group.Genistein attenuated IMN-induced gastropathy in rats by reducing inflammation, decreasing oxidative stress, restoring mucoprotective function, and improving gastric histopathology.This is an experimental study of the effect of NSAIDs in gastropathy. This study demonstrated the efficacy of genistein in treatment of NSAIDs-induced gastropathy. Genistein efficacy is reflected in the attenuation of histological alterations, with improvement in key biological parameters involved in the pathogenesis of NSAIDs gastropathy. Abbreviations used: NSAIDs: Non-steroidal anti-inflammatory drugs; IMN: Indomethacin; COX: Cyclooxygenase; TNF: Tumor necrosis factor; ICAM: Intercellular adhesion molecule; iNOS: Inducible nitric oxide synthase; MDA: Malondialdehyde; CINC: Cytokine-induced neutrophil chemoattractant.