Attenuated Expression Of The Tight Junction Proteins Is Involved In Clopidogrel-induced Gastric Injury Through P38/MAPK Activation

Background and Aims: Clopidogrel is widely used for antiplatelet andantithrombotic therapy which could induce several gastrointestinalcomplications, but the mechanisms remain unknown. The tight junctionscreate the paracellular permeability that is breached when thegastrointestinal injured, including increased gastrointestinal permeability.Thus the effect of Clopidogrel-induced gastric barrier disruption inhuman gastric epithelial cell was elucidated in this study.Methods: In this study, we used human gastric epithelial cell line GES-1that expresses zonula occludens (ZO)-1and Occludin as the experimentalmodel. GES-1cells were treated with Clopidogrel, and then wedetermined cell proliferation by MTT assay; apoptosis by flow cytometry;expression of Occludin and ZO-1by immunofluorescent and western blot;expression of phosphorylation of ERK, JNK, p38by western blot. Wealso measured epithelial permeability using FITCH-labeled dextranquantified by flow cytometry. Results: Clopidogrel inhibited the proliferation of GES-1cells in a doseand time dependent manner and decreased the expression of Occludin,ZO-1. The dextran permeability was increased. BothClopidogrel-mediated permeability and phosphorylation of p38MAPKwere significantly attenuated by SB-203580(a p38MAPK inhibitor)(P<0.05), neither by U-0126(a MEK1inhibitor) nor SP-600125(a JNKinhibitor). And the Clopidogrel-induced decrease in Occludin and ZO-1proteins was partly abolished by SB-203580pretreatment.Conclusion: These results demonstrate for the first time that attenuatedexpression of the TJ proteins occludin and ZO-1in human gastricepithelial cells could be involved in clopidogrel-induced gastric mucosalinjury through activation of the p38MAPK pathway.