Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 90, Issue -, Pages 38-46Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.11.034
Keywords
Atrial fibrillation; Lipids; Electrical remodeling; MicroRNA; Gap junction
Categories
Funding
- Program for Improvement of Research Environment for Young Researchers from Special Coordination Funds for Promoting Science and Technology [25461045, 26293052]
- Research Grant from Fukuda Memorial Foundation
- Translational Research Promotion Grant from The Japanese Circulation Society
- Grants-in-Aid for Scientific Research [15K15049, 26293052, 15H04684] Funding Source: KAKEN
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Background: Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and AF has not been fully investigated. Methods: Adult male mice were fed a high-fat diet (HFD) or vehicle (NC) for 2 months. Electrocardiography and in vivo electrophysiological study were performed. Mice were then sacrificed for quantification of mRNA, microRNA, and protein in atria, in addition to histological analysis. Conduction velocity (CV) in right atrium was measured by optical mapping in Langendorff perfused hearts. Cultured atrial cardiomyocytes were treated with palmitate with or without a specific microRNA inhibitor. Twelve hours after stimulation, cells were lysed, and subjected to analysis with qPCR and Western blotting. Results: HFD mice showed prolonged P wave duration, increased inducibility of sustained atrial tachycardia, and reduced atrial CV than NC mice. HFD mice also showed increased expression in inflammatory cytoldnes, whereas fibrotic area and signals relating fibrosis were not changed. HFD mice demonstrated reduced expression of Cx40 in mRNA and protein levels, and its lateralized expression in atria. MicroRNA array analysis revealed that miR-27b expression was up-regulated in HFD mice, and luciferase assay confirmed the direct interaction between miR-27b and Cx40 3'UTR. In palmitate-stimulated atrial cardiomyocytes, miR-27b up-regulation and Cx40 down-regulation were observed, while expression of inflammatory cytokines was not altered. Inhibition of miR-27b with antisense oligonucleotides reversed the alteration caused by palmitate stimulation. Conclusion: HFD may increase the vulnerability to atrial arrhythmia by down-regulation of Cx40 via miR-27b, rather than fibrosis, which is independent of inflammation. (C) 2015 Elsevier Ltd. All rights reserved.
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