lncRNA ZNF593-AS inhibits cardiac hypertrophy and myocardial remodeling by upregulating Mfn2 expression
Xiang Nie1,2, Jiahui Fan1,2, Yanwen Wang1,2, Rong Xie1,2, Chen Chen1,2, Huaping Li1,2(), Dao Wen Wang1,2()
1. Division of Cardiology, Department of Internal Medicine, 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, Wuhan 430030, China
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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