Effect Of Ticagrelor On Human Gastric Mucosal Epithelial Cells GES-1

Background and Aims:Ticagrelor is widely used for antiplatelet and antithrombotic therapy since 2012.However,it also has many side effects in clinical use such as gastrointestinal bleeding,dyspnea,arrhythmiaand abnornal renal function,the mechanisms of which remain unknown.The tight junctions plays an important role in the mucosal barrier,when the gastric epithelial cells injured,the mucosal barrier injured either.In this study,we want to elucidat the effect of Ticagrelor-induced gastric barrier disruption in human gastric epithelial cell.Methods:Serum was separated from a patient taking ticagrelor 180mg/d after 2h,and then,5%,10%,15%and 20%concentrations of ticagrelor-contained serum were prepared.The serum separated from the same patient before taking ticagrelor was taken as control.After incubated with serum containing ticagrelor for 24,48 and 72h,the inhibition rate of GES-1 cells was examined using methylthiazolyldiphenyl-tetrazolium(MTT)assay.The morphology changes ofGES-1 cells treated with different concentrations of ticagrelor for 24 hours were observed under an inverted phase contrast microscope.Transmission electron microscopy is used to observe the changes of tight junction.Flow cytometry was used to detect cell apoptosis after GES-1 cells incubated with serum containing ticagrelor for 24h,expression of Occludin and ZO-1 was detected by immunofluorescent and western blot;Results:Ticagrelor inhibited the proliferation of GES-1 cells in a concentration-dependent manner(p<0.05),but not in a time-dependent manner(p>0.05).After treated with Ticagrelor,GES-1 cells became round and suspended,some of which showed nuclear condensation in a dose-dependent manner.Moreover,in the ticagrelor group,the tight junction was injured.The apoptosis rate of GES-1 cells increased in a dose dependent manner after treated with ticagrelor.Further,the expression of Occludin and ZO-1 was reduced in Ticagrelor treated cells.Conclusion:These results demonstratethat attenuated expression of the TJ proteins Occludin and ZO-1 in human gastric epithelial cells could be involved in Ticagrelor-induced gastric mucosal injury.