Estrogen via GPER downregulated HIF-1a and MIF expression, attenuated cardiac arrhythmias, and myocardial inflammation during hypobaric hypoxia.

BACKGROUND: The human body is highly dependent on adequate oxygenation of the cellular space for physiologic homeostasis mediation. The insufficient oxygenation of the cellular space leads to hypoxia. Hypobaric hypoxia (HH) is the reduction in oxygen partial pressure and atmospheric pressure during ascent to high altitudes. This state induces a maladaptive response. Women and how hormones like estrogen influence hypoxia have not been explored with most research being conducted on males. In this study, we investigated the effects of estrogen and GPER on HIF-1a and MIF expression, cardiac arrhythmias, and inflammation during hypobaric hypoxia. METHODS: Ovariectomy and SHAM operations were done on FVB wild-type (WT) female mice. 2 weeks after the operation, the mice were treated with estrogen (40 mg/kg) as a therapeutic intervention and placed in a hypoxic chamber at an altitude of 6000 m for 7 days. Cardiac electrical activity was assessed using electrocardiography. Alterations in protein expression, inflammatory, and GPER pathways were investigated using western blotting, ELISA, and immunofluorescence. Histological assessment was performed using Masson's trichrome staining. Peritoneal macrophages were isolated for in vitro study. RESULTS: Under hypobaric hypoxia (HH), the ovariectomized (OVX) group showed increased macrophage migration inhibitory factor (MIF) and hypoxia-inducible factor-1 alpha (HIF-1α) expression. In contrast, these factors were downregulated in the estrogen-treated and control groups. HH also caused cardiac inflammation and fibrosis, especially in the OVX + HH group, which had elevated proinflammatory cytokines (IL-1β, IL-6, TNF-α) and decreased anti-inflammatory cytokines (TGF-β, IL-10). Inhibition with G15 (a GPER antagonist) increased MIF and HIF-1α, whereas activation with G1 (a GPER agonist) decreased their expression, highlighting GPER's crucial role in regulating MIF during HH. CONCLUSION: Estrogen regulates HIF-1α and MIF expression through the GPER during hypobaric hypoxia, suggesting a potential therapeutic pathway to mitigate maladaptive responses during high-altitude ascent.