可溶性环氧化物水解酶抑制剂通过下调心肌梗死后小鼠模型中的 microRNA-29 而上调 KCNJ12 和 KCNIP2。

A Soluble Epoxide Hydrolase Inhibitor Upregulated KCNJ12 and KCNIP2 by Downregulating MicroRNA-29 in a Mouse Model of Myocardial Infarction.

机构信息

Department of Internal Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha.

Department of Geratology, The Third Hospital of Changsha, Changsha, Hunan, China.

出版信息

Heart Surg Forum. 2020 Aug 12;23(5):E579-E585. doi: 10.1532/hsf.2999.

DOI:10.1532/hsf.2999

PMID:32990585

Abstract

BACKGROUND

Soluble epoxide hydrolase inhibitors (sEHi) have anti-arrhythmic effects, and we previously found that the novel sEHi t-AUCB (trans-4[-4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid) significantly inhibited ventricular arrhythmias after myocardial infarction (MI). However, the mechanism is unknown. It's known that microRNA-29 (miR-29) participates in the occurrence of arrhythmias. In this study, we investigated whether sEHi t-AUCB was protective against ischemic arrhythmias by modulating miR-29 and its target genes KCNJ12 and KCNIP2.

METHODS

Male 8-week-old C57BL/6 mice were divided into five groups and fed distilled water only or distilled water with t-AUCB of different dosages for seven days. Then, the mice underwent MI or sham surgery. The ischemic region of the myocardium was obtained 24 hours after MI to detect miR-29, KCNJ12, and KCNIP2 mRNA expression levels via real-time PCR and KCNJ12 and KCNIP2 protein expression levels via western blotting.

RESULTS

MiR-29 expression levels were significantly increased in the ischemic region of MI mouse hearts and the mRNA and protein expression levels of its target genes KCNJ12 and KCNIP2 were significantly decreased. T-AUCB prevented these changes dose-dependently.

CONCLUSION

The sEHi t-AUCB regulates the expression levels of miR-29 and its target genes KCNJ12 and KCNIP2, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmia.

摘要

背景

可溶型环氧化物水解酶抑制剂（sEHi）具有抗心律失常作用，我们之前发现新型 sEHi t-AUCB（反式-4[-4-（3-金刚烷-1-基-脲基）-环己氧基]-苯甲酸）可显著抑制心肌梗死（MI）后的室性心律失常。然而，其机制尚不清楚。已知 microRNA-29（miR-29）参与心律失常的发生。在这项研究中，我们通过调节 miR-29 及其靶基因 KCNJ12 和 KCNIP2，研究了 sEHi t-AUCB 是否通过调节 miR-29 及其靶基因 KCNJ12 和 KCNIP2 对缺血性心律失常起保护作用。

方法

雄性 8 周龄 C57BL/6 小鼠分为五组，分别给予蒸馏水或不同剂量的 t-AUCB 连续灌胃 7 天，然后进行 MI 或假手术。MI 后 24 小时取缺血区心肌，通过实时 PCR 检测 miR-29、KCNJ12 和 KCNIP2 mRNA 表达水平，通过 Western blot 检测 KCNJ12 和 KCNIP2 蛋白表达水平。