Effect of mitochondrial translocator protein TSPO on LPS-induced cardiac dysfunction

Xingyue Li, School of Materials Science and Engineering,SouthwestJiaotong University, Chengdu Sichuan, PR China; Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China.
Xiao Chen, Department of Geriatrics, General Hospital of Western Theater Command, Chengdu, Sichuan, PR China.
Feng-Yuan Yang, Department of Nephrology, General Hospital of Western Theater Command, Chengdu, Sichuan, PR China.
Tingting Shu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Lintao Jiang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Bo He, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Ming Tang, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Xingbing Li, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
Dandong Fang, Department of Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210000, PR China.
Pedro A. Jose, The George Washington University School of Medicine & Health Sciences.
Yu Han, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of China, Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China. Electronic address: hanyu@tmmu.edu.cn.
Yongjian Yang, School of Materials Science and Engineering,SouthwestJiaotong University, Chengdu Sichuan, PR China; Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China. Electronic address: yangyongjian38@sina.com.
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), Chongqing, PR China; Key Laboratory of Geriatric Cardiovascular and Cerebrovascular Disease Research, Ministry of Education of 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. Electronic address: zengchunyu@tmmu.edu.cn.

Document Type

Journal Article

Publication Date

10-9-2024

Journal

Journal of advanced research

DOI

10.1016/j.jare.2024.10.004

Keywords

Mitochondrial function; PROTAC; Sepsis-induced cardiac dysfunction; TSPO; VDAC oligomerization

Abstract

INTRODUCTION: Sepsis-induced cardiac dysfunction is one of the most serious complications of sepsis. The mitochondrial translocator protein (TSPO), a mitochondrial outer membrane protein, is widely used as a diagnostic marker of inflammation-related diseases and can also lead to the release of inflammatory components. However, whether TSPO has a therapeutic effect on sepsis-induced cardiac dysfunction is unclear. OBJECTIVES: The aim of this study is to investigate the involvement of TSPO in the pathogenesis of sepsis-induced cardiac dysfunction and elucidate its underlying mechanism, as well as develop therapeutic strategies targeting TSPO for the prevention and treatment of sepsis-induced cardiac dysfunction. METHODS: The sepsis-induced cardiac dysfunction model was established by intraperitoneal injection of lipopolysaccharide (LPS) in C57BL/6 mice (LPS-induced cardiac dysfunction, LICD). TSPO knockout mice were constructed,and the effects of TSPO was detected by survival rate, echocardiography, HE staining, mitochondrial electron microscopy, TUNEL staining. TSPO-binding proteins were identified by co-immunoprecipitation and mass spectrometry. The mechanisms underlying between TSPO and voltage-dependent anion channel (VDAC) was studied through western blot and immunofluorescence. Proteolysis-Targeting Chimeras (PROTAC) technology was used to construct TSPO-PROTAC molecules that can degrade TSPO. RESULTS: Our present study found that LPS increased cardiac TSPO expression. Knockout of TSPO in C57BL/6 mice with LICD attenuated the cardiac pathology, mitochondrial dysfunction, and apoptosis of cardiomyocytes and significantly improved cardiac function and survival rate. Co-immunoprecipitation and mass spectrometry identified VDAC as a TSPO binding protein.Down-regulation of TSPO reduced PKA-mediated VDAC phosphorylation and VDAC oligomerization, ameliorated mitochondrial function, and reduced cardiomyocyte apoptosis. The study has clinical translational potential, because administration of TSPO-PROTAC to degrade TSPO improved cardiac function in mice with LICD. CONCLUSION: This study elucidated the effect of TSPO in LICD, providing a new therapeutic strategy to down-regulate TSPO by administration of TSPO-PROTAC for the prevention and treatment of LICD.

Department

Medicine

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