Attenuation of Sepsis-Induced Cardiomyopathy by Regulation of MicroRNA-23b Is Mediated Through Targeting of MyD88-Mediated NF-κB Activation

Abstract

Myocardial cell injury or cardiomyopathy is associated with excessive inflammatory response and apoptosis of cardiac myocytes during sepsis. MicroRNA-23b (miR-23b) is a multifunctional miRNA that is considered to regulate immunosuppression in sepsis. The aim of this study was to examine the effect of miR-23b on cardiomyopathy induced by sepsis and to explore the potential mechanism involved. Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP), and the level of miR-23b at different time points was measured by quantitative real-time polymerase chain reaction (qPCR). Then, we overexpressed miR-23b in vivo and in vitro. The rats were subjected to CLP 7 days after transfection. Cardiac function, inflammatory response, and heart tissues were examined 3 days thereafter. In an in vitro experiment, H9C2 cardiomyoblasts were stimulated with lipopolysaccharide (LPS) after transfection of miR-23b, following which apoptosis and the level of NF-κB were analyzed. The expression of miR-23b was upregulated during polymicrobial sepsis, and transfection of miR-23b lentivirus improved the outcome of sepsis-induced cardiomyopathy by attenuating inflammatory responses and protecting against histopathological damage. In in vitro experiments, elevated miR-23b inhibited excessive apoptosis of cardiomyocytes, which may be because activation of the NF-κB signaling pathway was inhibited by the decreased levels of TRAF6 and IKKβ. Therefore, miR-23b improved sepsis-induced cardiomyopathy by attenuating the inflammatory response, suppressing apoptosis, and preventing NF-κB activation via targeted inhibition of TRAF6 and IκκB. These results indicated that miR-23b may represent a novel therapeutic approach for clinical treatment of sepsis-induced cardiomyopathy.

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Data Availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

BNP:

Brain natriuretic peptide

CK-MB:

Creatine kinase-MB

CLP:

Cecal ligation and puncture

CO:

Cardiac output

EF:

Ejection fraction

ELISA:

Enzyme-linked immunosorbent assay

EMSA:

Electrophoretic mobility shift assay

ICAM-1:

Intercellular cell adhesion molecule 1

LPS:

Lipopolysaccharide

MIF:

Migration inhibitory factor

miR-23b:

MicroRNA-23b

NF-κB:

Nuclear factor kappaB

qPCR:

Quantitative real-time polymerase chain reaction

SIC :

Sepsis-induced cardiomyopathy

TLR:

Toll-like receptor

VCAM-1:

Vascular cell adhesion molecule 1

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81871593 to YFC), Theory E Emergency Medical Research Fund of China (Grant No. R2015026 to CC), and Tianjin Medical University General Hospital Fund of China (Grant No. ZYYFY2015010 to CC, ZYYFY2016026 to YZ).

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CC performed experiments, analyzed data, prepared figures, and wrote the manuscript. YZ, LJW, YFC, and STS performed experiments and analyzed data. CFY performed the histological examination of the heart tissues. HJ designed experiments, analyzed data, prepared figures, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Heng Jin.

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The authors declare that they have no conflicts of interest.

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All experimental manipulations were undertaken in accordance with the Guide for the Care and Use of Medical Laboratory Animals (Ministry of Health, P.R. China, 1998), with the approval of the Scientific Investigation Board, Tianjin Medical University General Hospital, Tianjin, China.

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Cao, C., Zhang, Y., Chai, Y. et al. Attenuation of Sepsis-Induced Cardiomyopathy by Regulation of MicroRNA-23b Is Mediated Through Targeting of MyD88-Mediated NF-κB Activation. Inflammation 42, 973–986 (2019). https://doi.org/10.1007/s10753-019-00958-7

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KEY WORDS

  • microRNA-23b
  • sepsis-induced cardiomyopathy
  • inflammatory response
  • NF-κB
  • TRAF6
  • IκκB