Chronic Atrial Fibrillation Increases microRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current
Background—Atrial fibrillation (AF) is characterized by progressive atrial structural and electrical changes (atrial remodeling) that favor arrhythmia recurrence and maintenance. Reduction of L-type Ca2+ current (ICa,L) density is a hallmark of the electrical remodeling. Alterations in atrial microRNAs could contribute to the protein changes underlying AF-induced atrial electrical remodeling. This study was undertaken to compare miR-21 levels in isolated myocytes from atrial appendages obtained from sinus rhythm (SR) and chronic AF (CAF) patients and to determine whether L-type Ca2+ channel subunits are targets for miR-21.
Methods and Results—qPCR analysis showed that miR-21 was expressed in human atrial myocytes from SR patients and that its expression was significantly greater in CAF myocytes. There was an inverse correlation between miR-21 and CACNA1C expression and ICa,L density. Computational analyses predicted that CACNA1C and CACNB2 could be potential targets for miR-21. Luciferase reporter assays demonstrated that miR-21 produced a concentration-dependent decrease in the luciferase activity in CHO cells transfected with CACNA1C and CACNB2 3'UTR regions. miR-21 transfection in HL-1 cells produced changes in ICa,L properties qualitatively similar to those produced by CAF (i.e., a marked reduction of ICa,L density and shift of the inactivation curves to more depolarized potentials).
Conclusions—Our results demonstrated that CAF increases miR-21 expression in enzymatically isolated human atrial myocytes. Moreover, it decreases ICa,L density by downregulating Ca2+ channel subunits expression. These results suggested that this microRNA could participate in the CAF-induced ICa,L downregulation and in the action potential duration shortening that maintains the arrhythmia.
- L-type calcium current
- chronic atrial fibrillation
- atrial fibrillation
- atrial myocyte
- calcium channel
- Received October 11, 2013.
- Revision received June 16, 2014.
- Accepted June 20, 2014.