MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation
Open Access
- 1 April 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (5), 1939-1951
- https://doi.org/10.1172/jci62185
Abstract
Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.1, KCNJ2. We found that miR-26 was downregulated in atrial samples from AF animals and patients and this downregulation was accompanied by upregulation of IK1/KIR2.1 protein. miR-26 overexpression suppressed expression of KCNJ2/KIR2.1. In contrast, miR-26 knockdown, inhibition, or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-26 target. Knockdown of endogenous miR-26 promoted AF in mice, whereas adenovirus-mediated expression of miR-26 reduced AF vulnerability. Kcnj2-specific miR-masks eliminated miR-26–mediated reductions in Kcnj2, abolishing miR-26’s protective effects, while coinjection of a Kcnj2-specific miR-mimic prevented miR-26 knockdown-associated AF in mice. Nuclear factor of activated T cells (NFAT), a known actor in AF-associated remodeling, was found to negatively regulate miR-26 transcription. Our results demonstrate that miR-26 controls the expression of KCNJ2 and suggest that this downregulation may promote AF.Keywords
This publication has 50 references indexed in Scilit:
- Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial FibrillationCirculation, 2012
- miR-605joins p53 network to form a p53:miR-605:Mdm2 positive feedback loop in response to stressThe EMBO Journal, 2011
- Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targetsThe FASEB Journal, 2010
- Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus InfectionScience, 2010
- Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer ModelCell, 2009
- Bestrophin Cl− channels are highly permeable to HCO3−American Journal of Physiology-Cell Physiology, 2008
- MicroRNA-133 controls cardiac hypertrophyNature Medicine, 2007
- The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2Nature Medicine, 2007
- A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failureProceedings of the National Academy of Sciences of the United States of America, 2006
- Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA TargetsCell, 2005