Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 5, Pages 1939-1951Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI62185
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Funding
- Canadian Institute of Health Research [MOP 44365]
- European-North American Atrial Fibrillation Research Alliance (ENAFRA) of Fondation Leducq [07CVD03]
- Quebec Heart and Stroke Foundation
- Creative Research Groups of the National Natural Science Foundation of China [81121003]
- National Natural Science Foundation of China [81130088, 30971252]
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Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (I-K1) 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 I-K1/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 dovvnregulation may promote AF.
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