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LncGBP9 knockdown alleviates myocardial inflammation and apoptosis in mice with acute viral myocarditis via suppressing NF-κB signaling pathway

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Abstract

Background

Myocardial inflammation and apoptosis are key processes in coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). Accumulating evidence reveals the essential roles of long noncoding RNAs (lncRNAs) in the pathogenesis of AVMC. Here, we aimed to evaluate the biological functions of a novel lncRNA guanylate-binding protein 9 (lncGBP9) in AVMC progression and further explore its underlying mechanisms.

Methods

Initially, mouse models of AVMC were constructed by CVB3 infection. The expression and localization of lncGBP9 in heart tissues were analyzed using RT-qPCR and FISH. Adeno-associated virus serotype 9 (AAV9)-mediated lncGBP9 knockdown was then employed to clarify its roles in survival, cardiac function, and myocardial inflammation and apoptosis. Moreover, the mRNA and protein levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) were detected by RT-qPCR and ELISA, and the regulation of lncGBP9 knockdown on the NF-κB signaling pathway was investigated by Western blotting. Using an in vitro model of HL-1 cardiomyocytes exposed to CVB3 infection, the effects of lncGBP9 knockdown on cell viability, inflammation, and apoptosis were further evaluated in vitro.

Results

Increased lncGBP9 expression was detected in the heart tissues of AVMC mice and CVB3-infected HL-1 cells, and was mainly located in the cytoplasm. Knockdown of lncGBP9 remarkably alleviated the severity of AVMC in CVB3-infected mice, as verified by improved cardiac function, and reduced myocardial inflammation and apoptosis. Additionally, lncGBP9 knockdown suppressed the NF-κB signaling pathway and consequently reduced productions of pro-inflammatory cytokines in vivo. In vitro functional assays further confirmed that lncGBP9 knockdown promoted cell viability, inhibited cell apoptosis, and reduced pro-inflammatory cytokines release in CVB3-infected HL-1 cells through suppressing NF-κB activation.

Conclusions

Collectively, lncGBP9 knockdown exerts anti-inflammatory and anti-apoptotic effects in CVB3-induced AVMC, which may be mediated in part via NF-κB signaling pathway. These findings highlight lncGBP9 as an attractive target for therapeutic interventions.

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Availability of data and materials

All data generated or analyzed during this study are included in this manuscript and its supplementary files.

Abbreviations

AVMC:

Acute viral myocarditis

CVB3:

Coxsackievirus B3

LncRNAs:

Long noncoding RNAs

LncGBP9:

LncRNA guanylate-binding protein 9

AAV9:

Adeno-associated virus serotype 9

FISH:

Fluorescence in situ hybridization

RT-qPCR:

Quantitative real-time PCR

ELISA:

Enzyme-linked immunosorbent assay

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Acknowledgements

We appreciate all participants who provided technical supports for our research.

Funding

This study was supported by Fujian Provincial Natural Science Foundation (2022J01402, 2020J011058), the Startup Fund for Scientific Research of Fujian Medical University (2020QH1191), and High-Level Hospital Foster Grants from Fujian Provincial Hospital of Fujian Province (2020HSJJ04).

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Author notes

  1. Yimin Xue and Jiuyun Zhang contributed equally to this work.

Authors and Affiliations

  1. Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, Fujian, China

    Yimin Xue, Jiuyun Zhang, Jun Ke, Lijuan Zeng, Kun Cheng, Xu Han, Falu Chen & Feng Chen

  2. Fourth Department of Critical Care Medicine, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China

    Yimin Xue, Lijuan Zeng & Kun Cheng

  3. Department of Emergency, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China

    Jiuyun Zhang, Jun Ke, Xu Han, Falu Chen & Feng Chen

  4. Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, 350001, Fujian, China

    Yimin Xue, Jiuyun Zhang, Jun Ke, Xu Han, Falu Chen & Feng Chen

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  1. Yimin Xue
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Contributions

YX and FC conceived and designed the study. YX, JZ, JK, LZ, KC, XH, and FC carried out the experimental studies and data collection. YX and JZ performed data analysis and drafted the manuscript. FC coordinated the study and reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Feng Chen.

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The authors declare that they have no competing interests.

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All procedures associated with the study were approved by the Animal Experimentation Ethics Committee of Shengli Clinical Medical College of Fujian Medical University.

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Xue, Y., Zhang, J., Ke, J. et al. LncGBP9 knockdown alleviates myocardial inflammation and apoptosis in mice with acute viral myocarditis via suppressing NF-κB signaling pathway. Inflamm. Res. 71, 1559–1576 (2022). https://doi.org/10.1007/s00011-022-01644-5

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