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LncRNA MALAT1 Regulates USP22 Expression Through EZH2-Mediated H3K27me3 Modification to Accentuate Sepsis-Induced Myocardial Dysfunction

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Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNA (lncRNA), has been confirmed to recruit enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) to regulate cardiomyocyte apoptosis in diabetic cardiomyopathy. However, whether the similar regulatory axis exists in sepsis-induced myocardial dysfunction (SIMD) has not been clearly established. The current study sought to define the mechanism governing MALAT1-mediated EZH2 in SIMD. MALAT1 was significantly upregulated in lipopolysaccharide-induced cardiomyocytes. Depletion of MALAT1 by caudal vein injection of small interfering RNA targeting MALAT1 alleviated myocardial injury in SIMD rats, restored cardiac function, reduced oxidative stress production and fibrosis, and inhibited inflammatory factors and apoptosis in myocardial tissues. Moreover, MALAT1 bound to EZH2 and promoted EZH2 activity in the nucleus of cardiomyocytes. EZH2 repressed ubiquitin-specific peptidase 22 (USP22) expression through H3K27me3 modification. EZH2 elevation aggravated the cardiac injury in SIMD rats, while USP22 upregulation inhibited the effect of EZH2, which reduced the cardiac injury in SIMD rats. Taken together, MALAT1 decreased USP22 expression by interacting with EZH2, thereby worsening SIMD, highlighting an attractive therapeutic strategy for SIMD.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Author notes

  1. Hong Xu and Wei Ye have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Division, Shandong Provincial Third Hospital, Jinan, 250031, Shandong, People’s Republic of China

    Hong Xu

  2. Department of Respiratory Medicine, Shandong Provincial Third Hospital, Jinan, 250031, Shandong, People’s Republic of China

    Wei Ye

  3. Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, No. 12, WuYingShan Middle Road, Tianqiao District, Jinan, 250031, Shandong, People’s Republic of China

    Baochang Shi

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  1. Hong Xu
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Contributions

HX: conception and design of the research, drafted manuscript and performed main experiment; WY: contribution to validation and analyzed data; BCS: contribution to visualization, prepared figures and interpreted results of experiments. All authors reviewed and approved the final version of manuscript.

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Correspondence to Baochang Shi.

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All authors declare that there are no competing interests in this study.

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All animal experiment protocols were approved by the Animal Care Committee of the Shandong Provincial Third Hospital in compliance with the guidelines proposed by the Guide for the Care and Use of Laboratory Animals.

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All authors reviewed and approved the final version of manuscript.

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Handling Editor: Y. James Kang.

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Xu, H., Ye, W. & Shi, B. LncRNA MALAT1 Regulates USP22 Expression Through EZH2-Mediated H3K27me3 Modification to Accentuate Sepsis-Induced Myocardial Dysfunction. Cardiovasc Toxicol 22, 813–830 (2022). https://doi.org/10.1007/s12012-022-09758-2

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  • DOI: https://doi.org/10.1007/s12012-022-09758-2

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