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ERG mediates the inhibition of NK cell cytotoxicity through the HLX/STAT4/Perforin signaling pathway, thereby promoting the progression of myocardial infarction

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Abstract

This study aimed to investigate the role of ERG in the HLX/STAT4/Perforin signaling axis, impacting natural killer (NK) cell cytotoxicity and myocardial infarction (MI) progression. NK cell cytotoxicity was assessed via co-culture and 51Cr release assays. Datasets GSE34198 and GSE97320 identified common differentially expressed genes in MI. NK cell gene expression was analyzed in MI patients and healthy individuals using qRT-PCR and Western blotting. ERG's regulation of HLX and STAT4's regulation of perforin were studied through computational tools (MEM) and ChIP experiments. HLX's influence on STAT4 was explored with the MG132 proteasome inhibitor. Findings were validated in a mouse MI model.

ERG, a commonly upregulated gene, was identified in NK cells from MI patients and mice. ERG upregulated HLX, leading to STAT4 proteasomal degradation and reduced Perforin expression. Consequently, NK cell cytotoxicity decreased, promoting MI progression. ERG mediates the HLX/STAT4/Perforin axis to inhibit NK cell cytotoxicity, fostering MI progression. These results provide vital insights into MI's molecular mechanisms.

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Abbreviations

MI:

Myocardial infarction

ERG:

E26-related gene

NK:

Natural killer

HLX:

H2.0-like homeobox

STAT4:

Signal transducer and activator of transcription 4

SMCs:

Smooth muscle inhibitory cells

TNF-α:

Tumor Necrosis Factor-alpha

IFN-γ:

Interferon-γ

FS:

Fractional shorter

LVEF:

Left ventricular ejection fraction

a-SMA:

Alpha-smooth muscle actin

vWF:

Von Willebrand factor

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

RT-qPCR:

Reverse transcription-quantitative polymerase chain reaction

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Acknowledgements

Thank the reviewers for their valuable comments on this article.

Funding

This study was supported by the natural science foundation of Liaoning Province (No. 2019-MS-10).

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Authors and Affiliations

  1. Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing Street, Shenyang, Liaoning, 110001, People’s Republic of China

    Liang Guo, Di Wu, Jianfen Shen & Yuan Gao

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  2. Di Wu
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Contributions

Liang Guo and Di Wu designed the study. Jianfen Shen and Yuan Gao collated the data, designed and developed the database, carried out data analyses and produced the initial draft of the manuscript. Liang Guo and Di Wu contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Yuan Gao.

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Ethical statement

All animal experiments mentioned above have been approved by the Ethics Committee of our institute (No. CMUXN2022801). All patients have informed consent and obtained approval from our Clinical Ethics Committee.

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The author declares no conflict of interest.

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Key points

1. ERG mediates the regulation of NK cell cytotoxicity through the HLX/STAT4/Perforin signaling axis.

2. ERG is significantly overexpressed, and peripheral blood NK cell cytotoxicity is reduced.

3. ERG promotes the expression of HLX and the proteasomal degradation of STAT4.

4. ERG suppresses NK cell cytotoxicity.

5. ERG promotes the progression of mouse MI.

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Guo, L., Wu, D., Shen, J. et al. ERG mediates the inhibition of NK cell cytotoxicity through the HLX/STAT4/Perforin signaling pathway, thereby promoting the progression of myocardial infarction. J Physiol Biochem 80, 219–233 (2024). https://doi.org/10.1007/s13105-023-00999-5

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