Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C.

BACKGROUND: Reduction in L-type Ca2+ current (ICa,L ) density is a hallmark of the electrical remodeling in atrial fibrillation (AF). The expression of miR-155, whose predicted target gene is the α1c subunit of the calcium channel (CACNA1C), was upregulated in atrial cardiomyocytes (aCMs) from patients with paroxysmal AF.The study is to determine miR-155 could target the gene expression of ICa,L and contribute to electrical remodeling in AF.

METHODS: The expression of miR-155 and CACNA1C was assessed in aCMs from patients with paroxysmal AF and healthy control. ICa,L properties were observed after miR-155 transfection in human induced pluripotent stem cell derived atrial cardiomyocytes (hiPSC-aCMs). Furthermore, an miR-155 transgene (Tg) and knock-out (KO) mouse model was generated to determine whether miR-155 was involved in ICa,L -related electrical remodeling in AF by targeting CACNA1C.

RESULTS: The expression level of miR-155 was increased, while the expression level of CACNA1C reduced in the aCMs of patients with AF. miR-155 transfection in hiPSC-aCMs produced changes in ICa,L properties qualitatively similar to those produced by AF. miR-155/Tg mice developed a shortened action potential duration and increased vulnerability to AF, which was associated with decreased ICa,L and attenuated by an miR-155 inhibitor. Finally, the genetic inhibition of miR-155 prevented AF induction in miR-155/KO mice with no changes in ICa,L properties.

CONCLUSIONS: The increased miR-155 expression in aCMs was sufficient for the reduction in the density of ICa,L and the underlying electronic remodeling. The inhibition of miR-155 prevented ICa,L -related electric remodeling in AF and might constitute a novel anti-AF approach targeting electrical remodeling.