MG53 protects against septic cardiac dysfunction by ubiquitinating ATF2,Journal of Advanced Research

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MG53 protects against septic cardiac dysfunction by ubiquitinating ATF2
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2025-03-17 , DOI: 10.1016/j.jare.2025.03.031
Miao Tian ₁ , Yu Shi ₁ , Xue Gong ₁ , Wenjie Tan ₁ , Xinyi Guo ₁ , Yinghong Chen ₁ , Peili Yang ₁ , Hongmei Ren ₁ , Qi Cai ₁ , Jianjie Ma ₂ , Chunyu Zeng ₃ , Gengze Wu ₄

Affiliation

Department 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.
Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
Department 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; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China; Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, PR China.
Department 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; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, 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.

中文翻译：

MG53 通过泛素化 ATF2 来预防脓毒性心功能不全

介绍

脓毒性心功能不全（SCD）是脓毒症最常见的并发症，已成为重症监护病房死亡的主要原因。肌肉特异性蛋白 mitsugumin-53 （MG53）已被确定为保护细胞完整性的“分子创可贴”。

目标

据报道，重组人 MG53 （rhMG53）预处理可预防盲肠结扎穿刺（CLP）引起的心脏功能损害。然而，MG53 是否能预防 SCD 仍有待进一步阐明。

方法

C57BL/6J 小鼠腹膜内注射脂多糖（LPS）生成 SCD 模型。静脉注射腺相关病毒过表达 MG53，腹膜内给予 rhMG53。超声心动图评估心脏功能，ELISA 和 Western blot 评估心脏炎症。通过实时定量 PCR （qPCR）和免疫共沉淀（co-IP）研究 MG53 的机制。

结果

我们目前的研究发现，SCD 小鼠心脏中 MG53 的表达低于对照组。过表达或外源性 MG53 治疗减轻了心功能不全，提高了 SCD 小鼠的存活率，并伴有病理变化的改善，减少了心肌细胞凋亡，并降低了血清或心脏中的炎症因子水平。从机制上讲，MG53 通过泛素化 ATF2（TLR4 的重要转录因子）来抑制 TLR4 转录活性，最终降低 TLR4 的表达。