MG53 protects against septic cardiac dysfunction by ubiquitinating ATF2

Area of Science:

• Cardiovascular Biology
• Sepsis Pathophysiology
• Molecular Medicine

Background:

• Septic cardiac dysfunction (SCD) is a major cause of death in intensive care units.
• Mitsugumin-53 (MG53) is a protein known for its role in maintaining cell integrity.
• Previous studies suggested recombinant human MG53 (rhMG53) may protect against cardiac damage, but its role in SCD requires clarification.

Purpose of the Study:

• To investigate the protective role of MG53 in a mouse model of septic cardiac dysfunction (SCD).
• To elucidate the underlying molecular mechanisms by which MG53 exerts its cardioprotective effects in sepsis.

Main Methods:

• Established a mouse model of SCD using lipopolysaccharide (LPS) injection.
• Administered MG53 via adeno-associated virus (AAV) for overexpression and intraperitoneal injection of rhMG53.
• Assessed cardiac function using echocardiography, inflammation via ELISA and Western blot, and molecular mechanisms using qPCR and co-immunoprecipitation.

Main Results:

• MG53 expression was decreased in the hearts of SCD mice.
• MG53 treatment (overexpression or rhMG53) improved cardiac function, survival rates, and reduced cardiomyocyte apoptosis and inflammation.
• MG53 inhibited Toll-like receptor 4 (TLR4) transcriptional activity by ubiquitinating its transcription factor ATF2, leading to decreased TLR4 expression.

Conclusions:

• MG53 demonstrates significant cardioprotective effects against sepsis-induced cardiac dysfunction.
• The mechanism involves the downregulation of TLR4 expression via ATF2 ubiquitination.
• MG53 represents a promising therapeutic target for treating septic cardiac dysfunction.