Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C

J Mol Cell Cardiol. 2021 Jun:155:58-65. doi: 10.1016/j.yjmcc.2021.02.008. Epub 2021 Feb 24.

Abstract

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.

Keywords: Atrial fibrillation; CACNA1C; Electrical remodeling; microRNA-155.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Animals
  • Atrial Fibrillation / diagnosis
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / physiopathology*
  • Biomarkers
  • Calcium Channels, L-Type / genetics*
  • Cell Differentiation / genetics
  • Cell Line
  • Disease Models, Animal
  • Disease Susceptibility
  • Electrocardiography
  • Female
  • Gene Expression Regulation*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Middle Aged
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • RNA Interference*

Substances

  • 3' Untranslated Regions
  • Biomarkers
  • CACNA1C protein, human
  • Calcium Channels, L-Type
  • MIRN155 microRNA, human
  • MicroRNAs