Soluble epoxide hydrolase inhibitors, t-AUCB, regulated microRNA-1 and its target genes in myocardial infarction mice
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Ya-Jun Gui1,*, Tao Yang2,*, Qiong Liu1, Cai-Xiu Liao3, Jing-Yuan Chen1, Ya-Ting Wang1, Jia-Hui Hu1 and Dan-Yan Xu1
1Department of Cardiology, Internal Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
2Department of Cardiology, Internal Medicine, Changsha Central Hospital, Changsha, Hunan 410011, China
3Department of Geratology, Internal Medicine, The Third Hospital of Changsha, Changsha, Hunan 410011, China
*These authors have contributed equally to this work
Dan-Yan Xu, email: email@example.com
Keywords: soluble epoxide hydrolase inhibitors, miR-1, ischemic arrhythmia
Received: February 22, 2017 Accepted: June 20, 2017 Published: September 18, 2017
Purpose: Soluble epoxide hydrolase inhibitors (sEHIs) had been demonstrated to produce cardioprotective effects against ischemia-induced lethal arrhythmias, but the exact mechanisms remain unknown. The present study was designed to investigate whether the beneficial effects of sEHIs are related to regulation of microRNA-1, which was a proarrhythmic factor in the ischemic heart.
Methods: A mousemyocardial infarction (MI) model was established by ligating the coronary artery. sEHI t-AUCB (0.2, 1, 5 mg/L in drinking-water) was administered daily seven days before MI. The incidence of arrhythmias was assessed by in vivo electrophysiologic studies. miR-1, KCNJ2 (encoding the K+ channel subunit Kir2.1), and GJA1 (encoding connexin 43 [Cx43]) mRNA were measured by real-time PCR; Kir2.1 and Cx43 protein were assessed by western blotting and immunohistochemistry.
Results: We demonstrated that sEHIs reduced the myocardium infarct size and incidence of inducible arrhythmias in MI mice. Up-regulation of miR-1 and down-regulation of KCNJ2/Kir2.1 and GJA1/Cx43 mRNA/protein were observed in ischemic myocaridum, whereas administration of sEHIs produced an opposite effect. In addition, miR-1 overexpression inhibited expression of the target mRNA and their corresponding proteins, whereas t-AUCB reversed the effects. Our results further revealed that PI3K/Akt signaling pathway might participate in the negatively regulation of miR-1 by sEHi.
Conclusions: We conclude that sEHIs can repress miR-1, thus stimulate expression of KCNJ2/Kir2.1 and GJA1/Cx43 mRNA/protein in MI mice, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmias.
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