Soluble epoxide hydrolase inhibitors, t-AUCB, regulated microRNA-1 and its target genes in myocardial infarction mice.

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.

Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis.

Background Statin treatment in association with physical exercise can substantially reduce mortality in dyslipidaemic individuals. However, the available data to compare the efficacy and safety of statins and exercise combination therapy with statin monotherapy are limited. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, Embase and the Cochrane Library from database inception until December 2016. We included randomised and non-randomised studies that compared the efficacy and safety of statins and exercise combination therapy with statin monotherapy in patients with dyslipidaemia. Standardised mean differences were calculated and pooled by means of fixed effects models. The risk of bias and heterogeneity among trials was also assessed. Seven articles were assessed in terms of the efficacy of therapy and 13 from the viewpoint of therapeutic safety. Results In terms of efficacy, statins and exercise combination decreased the incidence of diabetes mellitus, improved insulin sensitivity and inflammation, but caused no change in lipid profile compared to statins alone. In terms of safety, statins and exercise combination increased peak oxygen uptake (standardised mean difference 1.01, 95% confidence interval 0.46 to 1.57) compared to statins alone. In contrast to statin-induced myopathy, chronic exercise training prior to statin treatment could counteract statin-induced adverse effects in skeletal muscle. Conclusion Statins and exercise combination therapy is more effective than statin monotherapy in terms of insulin sensitivity, inflammation and exercise capacity. The small number of studies warrants the need for more randomised controlled trials evaluating the efficacy and safety of combination therapy.

Soluble epoxide hydrolase inhibitors might prevent ischemic arrhythmias via microRNA-1 repression in primary neonatal mouse ventricular myocytes.

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 (DAEDstainTM Dye) (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 IK1 was 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.