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MG53 protects against septic cardiac dysfunction by ubiquitinating ATF2
Miao Tian1, Yu Shi1, Xue Gong1
1Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Introduction:
Septic cardiac dysfunction (SCD) is the most common complication of sepsis, which has become the primary cause of death in intensive care units. The muscle-specific protein mitsugumin-53 (MG53) has been identified to protect cell integrity as a "Molecular Band-Aid".
Objectives:
The recombinant human MG53 (rhMG53) pretreatment has been reported to prevent cardiac function damage caused by cecal ligation and puncture (CLP). However, whether or not MG53 protects against SCD remains to be further clarified.
Methods:
C57BL/6J mice were intraperitoneally injected with lipopolysaccharide (LPS) to generate the SCD model. MG53 was overexpressed by intravenously injected adeno-associated virus, and the rhMG53 was administrated intraperitoneally. The cardiac function was evaluated by echocardiography, and the cardiac inflammation was assessed through ELISA and Western blot. The mechanisms of MG53 were studied by quantitative real-time PCR (qPCR) and co-immunoprecipitation (co-IP).
Results:
Our present study found that MG53 expression was lower in hearts from SCD mice than controls. Overexpression or exogenous MG53 treatment alleviated cardiac dysfunction, improved survival rate in SCD mice, accompanied with improved pathological changes, reduced cardiomyocyte apoptosis, and lowered inflammatory factor levels in serum or hearts. Mechanistically, MG53 inhibited TLR4 transcriptional activity by ubiquitinating ATF2, an essential transcriptional factor for TLR4, which ultimately reduced the expression of TLR4.
Conclusion:
MG53 protect the cardiac function against sepsis by down-regulation of TLR4 expression, via ubiquitination of ATF2, a TLR4 transcriptional factor, which might be a promising therapeutic approach for septic cardiac dysfunction.
Insights
Mitsugumin-53 (MG53) protects heart function during sepsis by reducing inflammation and improving survival. MG53 achieves this by inhibiting TLR4 expression through ATF2 ubiquitination, offering a potential therapy for septic cardiac dysfunction.
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.
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