Clopidogrel-Induced Gastric Mucosal Injury Associated with Endoplasmic Reticulum Stress in Rats

Clopidogrel is widely used as an antiplatelet agent for the prevention and treatment of arterial thrombotic diseases, but its clinical application may be limited by gastrointestinal adverse effects, including gastric mucosal injury. Because epithelial cell survival is essential for maintaining gastric mucosal integrity, we hypothesized that clopidogrel-induced gastric epithelial injury would be accompanied by alterations in ER stress- and apoptosis-related markers. To test this hypothesis, GES-1 human gastric epithelial cells were treated with different concentrations of clopidogrel, and cell viability, apoptosis, cell cycle distribution, and molecular changes were evaluated using the Cell Counting Kit-8 (CCK-8) assay, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In parallel, Sprague-Dawley rats were administered clopidogrel by gavage to establish an in vivo gastric injury model. Gastric mucosal pathological changes were assessed by hematoxylin and eosin staining, and serum inflammatory cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA). Clopidogrel reduced GES-1 cell viability, promoted apoptosis, and altered cell cycle progression. In rats, clopidogrel induced gastric mucosal erosion, edema, and inflammatory cell infiltration, accompanied by increased serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) levels. Clopidogrel also increased the expression of the ER stress markers C/EBP homologous protein (CHOP) and activating transcription factor 5 (ATF5), increased Bcl-2-associated X protein (Bax) expression, decreased B-cell lymphoma 2 (Bcl-2) expression, and elevated the Bax/Bcl-2 ratio in both gastric tissues and GES-1 cells. These findings suggest that clopidogrel-induced gastric mucosal injury is associated with increased ER stress-related marker expression and disruption of the Bax/Bcl-2 balance, although a direct causal ER stress-mitochondrial apoptosis pathway was not established in this study.