<br>LncRNA ZNF593-AS 通过抑制 IRF3 信号通路缓解糖尿病心肌病,Molecular Therapy - Nucleic Acids

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LncRNA ZNF593-AS 通过抑制 IRF3 信号通路缓解糖尿病心肌病
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2023-05-05 , DOI: 10.1016/j.omtn.2023.04.025
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}

Affiliation

糖尿病可直接诱发心脏损伤，导致心肌病。然而，糖尿病心肌病的治疗策略仍然有限。构建 ZNF593-AS 敲除和心肌细胞特异性转基因小鼠。此外，采用高脂饮食（HFD）诱导的糖尿病小鼠模型和另一种经典糖尿病小鼠模型 db/db 小鼠。ZNF593-AS 使用 GapmeR（一种修饰的反义寡核苷酸）沉默，同时使用重组腺相关病毒血清型 9 介导的基因递送系统过表达。还进行了转录组测序、 RNA 沉降测定和 RNA 免疫沉淀测定以研究潜在机制。ZNF593-AS 在糖尿病心脏中的表达降低。ZNF593-AS 在体外减弱棕榈酸诱导的心肌细胞凋亡。在 HFD 诱导的糖尿病小鼠中，ZNF593-AS 缺失加重了心功能不全，并增强了心脏凋亡和炎症。相比之下，HFD 诱导的心功能不全在 ZNF593-AS 转基因小鼠中得到改善。一致地，ZNF593-AS 在 db/db 小鼠中发挥相同的心脏保护作用。从机制上讲，ZNF593-AS 直接与干扰素调节因子 3 （IRF3）的功能域相互作用，并抑制脂肪酸诱导的 IRF3 磷酸化和激活，有助于改善心肌细胞死亡和炎症。总之，我们的结果确定了 ZNF593-AS 在糖尿病心肌病中的保护作用，表明了一个新的潜在治疗靶点。

"点击查看英文标题和摘要"

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

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.

更新日期：2023-05-05

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