Mechanisms underlying the estradiol mediated protection of yak oviduct epithelial cells against ER-Ca2+ imbalance.

Abstract

Background: Extreme weather events are occurring with increasing frequency worldwide. Oviduct epithelial cells (OECs), which provide nutrients and a microenvironment critical for reproductive processes such as fertilization and early embryonic development, are vulnerable to extreme hyperthermia climate. Mitigating heat induced damage to yak oviduct epithelial cells (YOECs) may thus contribute to improving reproductive health. Studies have shown that hyperthermia reduces SERCA protein levels, leading to ER-Ca²⁺ dyschondrosteosis and subsequent cellular injury; this phenomenon indicates that ER-Ca imbalance is a critical factor in cellular damage. Estradiol (E₂), which not only promotes the YOEC functions essential for fertilization and early embryonic development but also participates in calcium regulation, is hypothesized to alleviate ER-Ca²⁺ imbalance induced YOEC damage. To test this hypothesis, we compared the ER-Ca²⁺ distribution and hyperthermia/ hapsigargin (TG, a SERCA inhibitor)-mediated cellular damage in YOECs under high temperature conditions. Proteomic sequencing was employed to analyze protein level changes in TG treated YOECs with ER-Ca²⁺ imbalance before and after E₂ treatment, elucidating the mechanism whereby E₂ mitigates YOEC injury.

Results: E₂ can alleviate the damage in YOECs caused by TG. This effect is associated with perturbations in the restored serine 927 phosphorylation site in type 3 inositol 1,4,5-trisphosphate receptor (IP3R3). Restoration of the serine 927 phosphorylation site in IP3R3 leads to an increase in ER-Ca²⁺ levels, which activates the calmodulin phosphatase/nuclear factor of the activated T cells pathway and promotes cell function, and reduces YOECs apoptosis under ER-Ca²⁺ conditions.

Conclusion: Our research results indicate that E₂ protects YOECs under ER-Ca²⁺ imbalance by increasing the protein expression of IP3R3 serine 927, highlighting the close relationship between protein expression and phosphorylation modification during ER-Ca²⁺ imbalance. These findings deepen our understanding of ER-Ca²⁺ imbalance damage and lay the foundation for further research and mitigation of related diseases.