Abstract
BackgroundIt has been demonstrated that soluble epoxide hydrolase inhibitors (sEHIs) are protective against ischemia-induced lethal arrhythmias, but the mechanisms involved are unknown. Previously, we showed that sEHIs might reduce the incidence of ischemic arrhythmias by suppressing microRNA-1 (miR-1) in the myocardium. As miR-1 and miR-133 have the same proarrhythmic effects in the heart, we assumed that the beneficial effects of sEHIs might also relate to the regulation of miR-133.MethodsA mouse model of myocardial infarction (MI) was established by ligating the coronary artery. The sEHI t-AUCB (trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid) was administered daily for 7 days before MI. Myocardial infarct size and cardiac function was assessed at 24 h post-MI. The miRNA expression profiles of sham and MI mice treated with or without t-AUCB were determined by microarray and verified by real-time PCR. The incidence of arrhythmias was assessed by in vivo electrophysiologic studies. The mRNA levels of miR-133, its target genes (KCNQ1 [potassium voltage-gated channel subfamily Q member 1] and KCNH2 [potassium voltage-gated channel subfamily H member 2]), and serum response factor (SRF) were measured by real-time PCR; KCNQ1, KCNH2, and SRF protein levels were assessed by western blotting.ResultsWe demonstrated that the treatment with sEHIs could reduce infarct size, improve cardia function, and prevent the development of cardiac arrhythmias in MI mice. The expression levels of 14 miRNAs differed between the sham and MI groups. t-AUCB treatment altered the expression of eight miRNAs: two were upregulated and six were downregulated. Of these, the muscle-specific miR-133 was downregulated in the ischemic myocardium. In line with this, up-regulation of miR-133 and down-regulation of KCNQ1 and KCNH2 mRNA/protein were observed in ischemic myocaridum, whereas administration of sEHIs produced an opposite effect. In addition, miR-133 overexpression inhibited expression of the target mRNA, whereas t-AUCB reversed the effects. Furthermore, SRF might participate in the negative regulation of miR-133 by t-AUCB.ConclusionsIn MI mice, sEHI t-AUCB can repress miR-133, consequently stimulating KCNQ1 and KCNH2 mRNA and protein expression, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmias.
Highlights
It has been demonstrated that soluble epoxide hydrolase inhibitors are protective against ischemia-induced lethal arrhythmias, but the mechanisms involved are unknown
We previously reported that soluble epoxide hydrolase (sEH) inhibitors (sEHIs) have anti-arrhythmic effects by repressing the activation of nuclear factor κB (NF-κB)–mediated gene transcription in animal models of pressure-overload hypertrophy [10]
As miRNAs can affect the stability of specific target mRNAs through post-transcriptional repression, we investigated the effects of miR-133 on the expression of potassium voltage-gated channel subfamily Q member 1 (KCNQ1) and potassium voltage-gated channel subfamily H member 2 (KCNH2) mRNA
Summary
It has been demonstrated that soluble epoxide hydrolase inhibitors (sEHIs) are protective against ischemia-induced lethal arrhythmias, but the mechanisms involved are unknown. Most antiarrhythmic drugs have been challenged in the clinic due to limited effectiveness and proarrhythmic potential [1]. Several class III antiarrhythmic drugs prolong the QT interval and increase the risk of potentially lethal torsades de pointes (TdP) arrhythmias in patients with MI [2]. Several studies have documented the cardioprotective effects of sEHIs in preventing cardiac arrhythmias both in murine models with cardiac hypertrophy and with MI [10,11,12]. We previously reported that sEHIs have anti-arrhythmic effects by repressing the activation of nuclear factor κB (NF-κB)–mediated gene transcription in animal models of pressure-overload hypertrophy [10]. The exact mechanisms by which sEHIs exert their anti-arrhythmic effect after MI have not been studied
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