title: Soluble epoxide hydrolase inhibitors might prevent ischemic arrhythmias via microRNA-1 repression in primary neonatal mouse ventricular myocytes.
abstract: Ischemic arrhythmias are the main causes of sudden cardiac death. It has been reported that soluble epoxide hydrolase inhibitors (sEHis) could prevent arrhythmias; however, the underlying molecular mechanisms remain unclear. In recent years, the proarrhythmic role of microRNA-1 (miR-1) has been investigated. This study aimed to elucidate whether sEHis prevented ischemic arrhythmias by suppressing miR-1. The primary neonatal mouse ventricular myocyte model of miR-1 overexpression was established by incubating with agonist microONTM mmu-miR-1a-3p agomir (DAEDstainTMDye) (agomiR-1). The sEHi, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), was administered following miR-1 overexpression. Quantitative real-time PCR (qPCR) and western blotting were used to test alterations in the expression of miR-1 and its target mRNAs GJA1 and KCNJ2 and their respective encoded proteins connexin 43 (Cx43) and the K+channel subunit (Kir2.1). The whole-cell patch-clamp technique was used to record the alterations of the inward rectifying K+current (IK1). Compared with the control group, miR-1 levels were significantly increased in the agomiR-1 group (p < 0.05), which suggested the successful construction of the miR-1 overexpression model. Compared with the control group, the levels of GJA1 and KCNJ2 mRNAs and Cx43 and Kir2.1 proteins in the agomiR-1 group were significantly decreased, and IK1was significantly impaired (all p < 0.05). The miR-1 levels were dose-dependently decreased by t-AUCB, whereas t-AUCB dose-dependently increased the levels of GJA1 and KCNJ2 mRNAs and Cx43 and Kir2.1 proteins. Furthermore, t-AUCB restored the impaired IK1(all p < 0.05). In conclusion, the sEHi t-AUCB has the ability to down-regulate proarrhythmic miR-1 and up-regulate its target genes and proteins, eventually restoring IK1.
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, People's Hospital of Dongying, Dongying, Shandong 257000, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Ran
authors.initials: R
authors.lastname: Peng
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Mi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Wang
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Gui
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Cai-Xiu
authors.initials: CX
authors.lastname: Liao
authors.affiliation: Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. xudanyan02@163.com.
authors.forename: Dan-Yan
authors.initials: DY
authors.lastname: Xu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D001565:Benzoates / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D017202:Myocardial Ischemia / Q000150:complications*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D020011:Protective Agents / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D018031:Connexin 43; D004791:Enzyme Inhibitors; C543076:GJA1 protein, mouse; C489461:Kir2.1 channel; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D024661:Potassium Channels, Inwardly Rectifying; D020011:Protective Agents; D014508:Urea; D004851:Epoxide Hydrolases