Purpose: The role of GPER in sepsis-induced myocardial cell injury and its potential impact on the risk of death within 28 days in sepsis. Methods: An in vitro experiment was conducted to establish a sepsis-induced myocardial cell model. H9C2 myocardial cells were treated with 10 μg/ml lipopolysaccharide (LPS) for 24 hours. The effects of different concentrations of the GPER agonist G1 (1, 3, and 10 μmol/L) on cell viability, expression of inflammatory markers, cell apoptosis, and the NF-κB pathway were evaluated. A Mendelian randomization analysis was conducted using Single Nucleotide Polymorphism (SNPs) related to the GPER gene as instrumental variables to investigate the causal relationship between the GPER gene variations and sepsis (28-day death). Results: The results indicate that the group treated with LPS showed a significant decrease in myocardial cell viability, an increase in concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), higher apoptosis rates, and increased phosphorylation levels of NF-κB p65 (p-P65/P65) and IκB-α (p-IκB-α/IκB-α) compared to the control group (P < 0.05). These indicators were significantly reversed by low, medium, and high doses of G1 (P < 0.05), demonstrating a dose-dependent effect of G1. The protective effects of G1 were negated upon the addition of phorbol 12-myristate 13-acetate (PMA), indicating that its protective mechanism involves the inhibition of the NF-κB pathway. However, genetic evidence did not show a causal relationship between GPER gene variations and sepsis (28-day death) (P < 0.05). Conclusion: Activation of GPER mitigates sepsis-induced myocardial cell inflammation and apoptosis by inhibiting the NF-κB pathway. However, genetic evidence did not show a causal relationship between GPER gene variations and sepsis (28-day death).
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