MG53 protects against septic cardiac dysfunction by ubiquitinating ATF2 - Original Manuscript - Journal of Advanced Research

Sep 29, 2026

Septic cardiac dysfunction is a frequent, lethal complication of sepsis, yet targeted therapies remain limited. This study evaluates recombinant human MG53 (rhMG53) and overexpression of MG53 in a mouse SCD model induced by lipopolysaccharide. Outcomes include echocardiographic cardiac performance, survival, inflammation, and cardiomyocyte apoptosis. Mechanistically, MG53 suppresses TLR4 transcriptional activity by ubiquitinating ATF2, reducing TLR4 expression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

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Introduction

Objectives

Methods

Results

Conclusion

Journal of Advanced Research 79 (2026) 263–275 Contents lists available at ScienceDirect Journal of Advanced Research journal [homepage: www. elsevier. com/locate/jare](homepage: www. elsevier. com/locate/jare) Original Manuscript MG53 protects against septic cardiac dysfunction by ubiquitinating ATF2 Miao Tian a,b,c, 1, Yu Shi a,b,c, 1, Xue Gong a,b,c, Wenjie Tan a,b,c, Xinyi Guo a,b,c, Yinghong Chen a,b,c, Peili Yang a,b,c, Hongmei Ren a,b,c, Qi Cai a,b,c, Jianjie Ma d, Chunyu Zeng a,b,c,e,f,g,⁎, Gengze Wu a,b,c,e,⁎ a Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China b Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing, PR China c Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China d Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA e State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China f Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China g Department of Cardiology, The First Afﬁliated Hospital of Kunming Medical University, Kunming, Yunnan, PR China h i g h l i g h t s • E3 ubiquitination ligase MG53 is highly expressed in heart and decreased in sepsis. • Recombinant human MG53 signiﬁcantly improve sepsis-impaired cardiac function and survival rate of mice. • MG53 alleviate inﬂammation and apoptosis by inhibiting TLR4. • MG53 ubiquitinate transcriptional factor ATF2 via its RING domain. • RhMG53 is promising in the treatment of sepsis. g r a p h i c a l a b s t r a c t a r t i c l e i n f o Article history: Received 22 December 2024 Revised 16 March 2025 Accepted 16 March 2025 Available online 17 March 2025 Keywords: Septic cardiac dysfunction MG53 Inﬂammation Apoptosis TLR4 ATF2 a b s t r a c t 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 therhMG53 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. ⁎ Corresponding authors at: Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China. E-mail addresses: [zengchunyu@tmmu.edu.cn](zengchunyu@tmmu.edu.cn) (C. Zeng), [wugengze@tmmu.edu.cn](wugengze@tmmu.edu.cn) (G. Wu). 1 Contribute equally to this work. [https://

FAQs

What is septic cardiac dysfunction and why is it important in sepsis?

Septic cardiac dysfunction is a common complication of sepsis and the leading cause of death in septic patients. Mortality is much higher when cardiac dysfunction is present.

How did the study model septic cardiac dysfunction in mice and deliver MG53?

C57BL/6J mice received intraperitoneal lipopolysaccharide to generate the SCD model. MG53 was overexpressed via intravenously injected adeno-associated virus, and rhMG53 was administered intraperitoneally.

What mechanism explains how MG53 protects the heart in septic cardiac dysfunction?

MG53 inhibits TLR4 transcriptional activity by ubiquitinating ATF2, a transcriptional factor for TLR4, which ultimately lowers TLR4 expression.

Sep 29, 2026

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