GPR30 Agonist G1 Mitigates Sepsis-Induced Cardiac Dysfunction by Inhibiting ACE2/c-FOS-Mediated Necroptosis in Female...

Area of Science:

• Cardiology
• Endocrinology
• Molecular Biology

Background:

• Sepsis is a life-threatening inflammatory condition with high mortality.
• Sepsis-induced myocardial dysfunction (SIMD) is a major cause of death.
• The protective mechanisms underlying sex differences in sepsis remain unclear.

Purpose of the Study:

• To investigate the role of G protein-coupled estrogen receptor 30 (GPR30) in female septic cardiac dysfunction.
• To elucidate the molecular pathways involved in GPR30-mediated protection against SIMD.

Main Methods:

• Utilized lipopolysaccharide (LPS) to induce sepsis in female wild-type and ACE2-knockout mice.
• Administered G1 agonist to activate GPR30.
• Assessed cardiac function, myocardial injury, and necroptosis.
• Investigated the role of STAT6, ACE2, and c-FOS using molecular techniques.

Main Results:

• GPR30 activation by G1 protected female hearts against LPS-induced SIMD.
• This protection was abolished in female ACE2-knockout mice, showing impaired cardiac function and increased necroptosis.
• GPR30 activation induced ACE2 transcription via STAT6.
• Inhibition of ACE2 and c-FOS reversed cardiac dysfunction and improved survival in ACE2-knockout mice.

Conclusions:

• GPR30 plays a crucial protective role in female hearts during sepsis.
• The GPR30/STAT6/ACE2/c-FOS pathway mediates protection against sepsis-induced necroptosis.
• This study provides novel insights into the sex-specific mechanisms of sepsis-related organ damage.