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 card...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.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.82100399,82100400,and 81790624)the project funded by China Postdoctoral Science Foundation(No.2021M701315).
文摘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.
