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lncRNA ZNF593-AS inhibits cardiac hypertrophy and myocardial remodeling by upregulating Mfn2 expression

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Abstract

lncRNA ZNF593 antisense (ZNF593-AS) transcripts have been implicated in heart failure through the regulation of myocardial contractility. The decreased transcriptional activity of ZNF593-AS has also been detected in cardiac hypertrophy. However, the function of ZNF593-AS in cardiac hypertrophy remains unclear. Herein, we report that the expression of ZNF593-AS reduced in a mouse model of left ventricular hypertrophy and cardiomyocytes in response to treatment with the hypertrophic agonist phenylephrine (PE). In vivo, ZNF593-AS aggravated pressure overload–induced cardiac hypertrophy in knockout mice. By contrast, cardiomyocyte-specific transgenic mice (ZNF593-AS MHC-Tg) exhibited attenuated TAC-induced cardiac hypertrophy. In vitro, vector-based overexpression using murine or human ZNF593-AS alleviated PE-induced myocyte hypertrophy, whereas GapmeR-induced inhibition aggravated hypertrophic phenotypes. By using RNA-seq and gene set enrichment analyses, we identified a link between ZNF593-AS and oxidative phosphorylation and found that mitofusin 2 (Mfn2) is a direct target of ZNF593-AS. ZNF593-AS exerts an antihypertrophic effect by upregulating Mfn2 expression and improving mitochondrial function. Therefore, it represents a promising therapeutic target for combating pathological cardiac remodeling.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Nos. 82100399, 82100400, and 81790624) and the project funded by China Postdoctoral Science Foundation (No. 2021M701315). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank colleagues in Dr. Wang’s group for various technical help and stimulating discussion during this investigation.

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  1. These authors contributed equally.

Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiang Nie, Jiahui Fan, Yanwen Wang, Rong Xie, Chen Chen, Huaping Li & Dao Wen Wang

  2. Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China

    Xiang Nie, Jiahui Fan, Yanwen Wang, Rong Xie, Chen Chen, Huaping Li & Dao Wen Wang

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  1. Xiang Nie
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Correspondence to Huaping Li or Dao Wen Wang.

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Conflict of interests Xiang Nie, Jiahui Fan, Yanwen Wang, Rong Xie, Chen Chen, Huaping Li, and Dao Wen Wang declare that they have no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed. All animal experimental protocols complied with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health as well as the Animal Research: Reporting of In Vivo Experiments guidelines. This study was approved by the Institutional Animal Research Committee of Tongji Medical College.

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Nie, X., Fan, J., Wang, Y. et al. lncRNA ZNF593-AS inhibits cardiac hypertrophy and myocardial remodeling by upregulating Mfn2 expression. Front. Med. (2024). https://doi.org/10.1007/s11684-023-1036-4

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