Clemastine fumarate alleviates endoplasmic reticulum stress through the Nur77/GFPT2/CHOP pathway after ischemia/reperfusion in rat hearts

Clemastine fumarate (CLE) is an H1 receptor (H1R) antagonist that is used clinically to treat various allergic disorders. It blocks histamine release from mast cells and inhibits H1R. Preliminary studies have shown that CLE can reduce myocardial ischemia/reperfusion (I/R) injury. In this study, we confirmed the efficacy of CLE against myocardial I/R injury using in vivo and in vitro examinations. To test the efficacy of CLE against myocardial I/R injury, we established a rat model of myocardial hypoxia/reperfusion injury. A series of assessments were conducted to determine cardiac function, measure areas of myocardial infarction, and analyze the histopathological changes. Additionally, we developed a rat model of cardiomyocyte hypoxia/reoxygenation (H/R); in both models, we quantified the expression levels of key markers and cardiac injury-specific proteins to assess the biochemical milieu influenced by CLE treatment. Our findings demonstrated that CLE reduced the expression of nerve growth factor-induced gene B (Nur77), glutamine-fructose-6-phosphate transaminase 2 (GFPT2), and C/EBP homologous protein (CHOP) and decreased the area of myocardial infarction and the degree of endoplasmic reticulum stress. CLE pretreatment ameliorated abnormal fibers and myocardial edema and reduced the inflammatory cell infiltration caused by I/R injury. While Nur77 overexpression aggravated cardiac function, these effects were ameliorated by the downregulation of Nur77. We anticipate that these results validate the hypothesis that CLE mitigates apoptosis and reduces endogenous stress within myocardial cells by modulating Nur77, GFPT2, and CHOP expression. These findings elucidate the therapeutic mechanisms by which CLE alleviates myocardial I/R injury. In addition, they will serve as a new theoretical foundation for developing future treatment strategies and enhancing clinical applications in cardiac care.