LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway

Rong Xie; Jiahui Fan; Jianpei Wen; Kunying Jin; Jiabing Zhan; Shuai Yuan; Yuyan Tang; Xiang Nie; Zheng Wen; Huaping Li; Chen Chen; Dao Wen Wang

doi:10.1016/j.omtn.2023.04.025

LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway

Mol Ther Nucleic Acids. 2023 May 5:32:689-703. doi: 10.1016/j.omtn.2023.04.025. eCollection 2023 Jun 13.

Authors

Rong Xie^{1

2}, Jiahui Fan^{1

2}, Jianpei Wen^{1

2}, Kunying Jin^{1

2}, Jiabing Zhan^{1

2}, Shuai Yuan^{1

2}, Yuyan Tang^{1

2}, Xiang Nie^{1

2}, Zheng Wen^{1

2}, Huaping Li^{1

2}, Chen Chen^{1

2}, Dao Wen Wang^{1

2}

Affiliations

¹ Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Wuhan 430030, China.

Abstract

Diabetes could directly induce cardiac injury, leading to cardiomyopathy. However, treatment strategies for diabetic cardiomyopathy remain limited. ZNF593-AS knockout and cardiomyocyte-specific transgenic mice were constructed. In addition, high-fat diet (HFD)-induced diabetic mouse model and db/db mice, another classic diabetic mouse model, were employed. ZNF593-AS was silenced using GapmeR, a modified antisense oligonucleotide, while overexpressed using a recombinant adeno-associated virus serotype 9-mediated gene delivery system. Transcriptome sequencing, RNA pull-down assays, and RNA immunoprecipitation assays were also performed to investigate the underlying mechanisms. ZNF593-AS expression was decreased in diabetic hearts. ZNF593-AS attenuated the palmitic acid-induced apoptosis of cardiomyocytes in vitro. In HFD-induced diabetic mice, ZNF593-AS deletion aggravated cardiac dysfunction and enhanced cardiac apoptosis and inflammation. In contrast, HFD-induced cardiac dysfunction was improved in ZNF593-AS transgenic mice. Consistently, ZNF593-AS exerted the same cardioprotective effects in db/db mice. Mechanistically, ZNF593-AS directly interacted with the functional domain of interferon regulatory factor 3 (IRF3), and suppressed fatty acid-induced phosphorylation and activation of IRF3, contributing to the amelioration of cardiac cell death and inflammation. In conclusion, our results identified the protective role of ZNF593-AS in diabetic cardiomyopathy, suggesting a novel potential therapeutic target.

Keywords: IRF3; MT: Non-coding RNAs; ZNF593-AS; cardiomyocytes; diabetes; diabetic cardiomyopathy; lncRNA.