糖尿病性心肌病
内部收益率3
炎症
转基因
转基因小鼠
细胞凋亡
内分泌学
糖尿病
癌症研究
心肌病
内科学
信号转导
医学
生物
细胞生物学
心力衰竭
受体
先天免疫系统
基因
生物化学
作者
Rong Xie,Jianping Fan,Jianpei Wen,Kunying Jin,Jiabing Zhan,Shuai Yuan,Yuyan Tang,Xiaowa Nie,Zheng Wen,Huaping Li,Chen Chen,Dao Wen Wang
标识
DOI:10.1016/j.omtn.2023.04.025
摘要
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.
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