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Interferon Regulatory Factor-2 Binding Protein 2 Ameliorates Sepsis-Induced Cardiomyopathy via AMPK-Mediated Anti-Inflammation and Anti-Apoptosis

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Abstract

Cardiomyopathy commonly occurs after sepsis and is closely associated with high mortality in clinic. Interferon regulatory factor-2 binding protein 2 (IRF2BP2) has been identified as a negative regulator of inflammation, but its role in septic cardiomyopathy is unknown. The current study aims to illuminate the regulatory function of IRF2BP2 on sepsis-induced cardiomyopathy and to explore the underlying mechanisms. Protein expression of IRF2BP2 in response to sepsis-induced cardiomyopathy was examined in the heart of mice challenged by LPS intraperitoneal injection. AAV9-delivered IRF2BP2 overexpression in the heart was applied to evaluate the regulatory role of IRF2BP2 in sepsis-induced myocardial depression, inflammatory response, and cell death. The molecular mechanisms underlying IRF2BP2-regulated cardiomyopathy were explored using western blot screening assay. Primary cardiomyocytes have been isolated to further confirm the role and mechanism of IRF2BP2 during septic cardiomyopathy. IRF2BP2 expression was dramatically increased in the heart of mice after LPS administration. AAV9-mediated IRF2BP2 overexpression significantly improved sepsis-induced cardiac dysfunction, inhibited inflammatory cell infiltration and cytokine production, and blocked cell death after LPS treatment. Mechanistically, IRF2BP2 activated AMPK signaling in cardiomyocytes, while inhibiting AMPK activation largely reversed IRF2BP2-benefited inflammatory suppression and cell survival. These findings clearly demonstrated that IRF2BP2 is a potent suppressor of sepsis-induced myocardial depression and related heart impairment. Targeting IRF2BP2 represents a promising therapeutic strategy for septic cardiomyopathy.

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Abbreviations

IRF2BP2:

interferon regulatory factor-2 binding protein 2

AAV:

adeno-associated virus

LPS:

lipopolysaccharide

CPC:

compound C

LVEDd:

left ventricular end-diastolic diameter

LVESd:

left ventricular end-systolic diameter

EF:

ejection fraction

FS:

fractional shortening

RT-qPCR:

Real-time quantitative polymerase chain reaction

TNF:

tumor necrosis factor

ILs:

interleukins

PVDF:

polyvinylidene fluoride

SD:

standard deviation

ANOVA:

analysis of variance

NF-κB:

nuclear transcription factor kappa B

P-P65:

phospho-nuclear transcription factor kappa B P65

T-P65:

total nuclear transcription factor kappa B P65

P-IκBα:

phospho-inhibitor of nuclear transcription factor kappa B α

T-IκBα:

total inhibitor of nuclear transcription factor kappa B α

Bcl2:

B cell lymphoma-2

Bax:

BCL2-Associated X protein

c-caspase3:

cleaved-caspase3

P-AMPK:

phospho-adenosine monophosphate-activated protein kinase

T-AMPK:

total-adenosine monophosphate-activated protein kinase

P-ACC:

phospho-acetyl coenzyme A carboxylase

T-ACC:

total-acetyl coenzyme A carboxylase

P-mTOR:

phospho-mammalian target of rapamycin

T-mTOR:

total-mammalian target of rapamycin

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

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Funding

This work was financially supported by the grant from National Natural Science Foundation of China (No. 81271348).

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Author notes

  1. Jie Xie and Chengla Yi contributed equally to this work.

Authors and Affiliations

  1. Trauma Center/Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, 1095 Jiefang avenue, Wuhan, 430030, China

    Tianyu Li, Qiang Luo, Li He, Chuntao Wang, Jie Xie & Chengla Yi

  2. Department of Pharmacy, The Seventh People’s Hospital of Chengdu, Chengdu, Sichuan, China

    Da Li

  3. Department of Intensive Care Unit, Tongji Hospital, Tongji Medical College of Huazhong, University of Science and Technology, 1095 Jiefang avenue, Wuhan, 430030, China

    Qingnian Li

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Contributions

Chengla Yi and Jie Xie contributed equally to this work as corresponding authors. Tianyu Li and Qiang Luo contributed equally to this work. Chengla Yi and Jie Xie conceived and designed all the experiments. Tianyu Li and Qiang Luo performed the experiments. Qiang Luo performed the revised experiments. Qiang Luo, Li He, Da Li, Qingnian Li, and Chuntao Wang analyzed the data and made the interpretation. Chengla Yi, Jie Xie, Tianyu Li, and Qiang Luo drafted and revised the article. All authors read and approved the final version.

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Correspondence to Chengla Yi.

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The authors declare that they have no conflict of interest.

Ethics Statement

All procedures involving animals were reviewed and approved by the Animal Care and Use Committee of Tongji Hospital of Huazhong University of Science and Technology and were performed according to the Declaration of Helsinki of the World Medical Association.The male C57BL6/J mice at the age of 10-12 weeks were applied in our experiments and were maintained in a standard specific-pathogen-free environment with 12-h light and 12-h dark cycle at the temperature of 20–26 °C. Food and water were accessed with ad libitum.

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Tianyu Li and Qiang Luo are co-first authors.

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Li, T., Luo, Q., He, L. et al. Interferon Regulatory Factor-2 Binding Protein 2 Ameliorates Sepsis-Induced Cardiomyopathy via AMPK-Mediated Anti-Inflammation and Anti-Apoptosis. Inflammation 43, 1464–1475 (2020). https://doi.org/10.1007/s10753-020-01224-x

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