Endocrine Abstracts

Background and aim: Sepsis, a leading global cause of mortality, involves life threatening multi-organ failure triggered by a dysregulated host response to infection. Cardiac dysfunction significantly contributes to this failure, primarily influenced by septic-induced metabolic dysregulation. Clinical studies suggest a less favorable outcome for males in sepsis, potentially linked to hormonal disparities, which remains unclear. This study aimed to explore the sex-related cardiac mechanisms driving septic-induced mortality.

Methods and results: Here, we unveil that while sepsis induces dysfunction, metabolic dysregulation, oxidative stress, and apoptosis in the heart, these effects are notably more pronounced in males than females. Detailed mechanistic experiments employing ovariectomized mice, β-estradiol(E2) administration, GPER-1⁺/⁺ (G protein-coupled estrogen receptor 1), and GPER-1^-/^- mice revealed that under lipopolysaccharide (LPS)-induced sepsis, E2 acting via GPER-1 enhances cardiac electrical activity, promotes PPARδ nuclear translocation, and subsequently ameliorates cardiac metabolism while mitigating oxidative stress and apoptosis in females. Furthermore, PPARδ specific activation using GW501516 in female GPER-1⁻/⁻ mice reduced oxidative stress, ultimately decreasing NLRP3 expression in the heart. Remarkably, targeted GPER-1 activation using G1 in males mirrors these benefits, improving cardiac electrical activity and function and ultimately enhancing survival rates during LPS-induced sepsis. By employing NLRP3⁺/⁺and NLRP3⁻/⁻ mice, we demonstrated that the targeted GPER-1 activation mitigated injury, enhanced metabolism, and reduced cardiac apoptosis in the heart of male mice via the downregulation of NLRP3.

Conclusion: Our findings collectively illuminate the different sex-specific mechanisms influencing septic mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries not only advance our understanding of sepsis regarding sex but also present a novel avenue for targeted interventions with potential translational impact.