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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 r...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706901/ https://www.ncbi.nlm.nih.gov/pubmed/29212255 http://dx.doi.org/10.18632/oncotarget.21831 |
Sumario: | 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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