title: Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure.
abstract: BACKGROUND
  Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI).
  
  
  RESULTS
  Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti-miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR-21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69-1595; median [Q1-Q3]) seconds to 3 (2-16) seconds (8 weeks after MI; P<0.05), and reduced atrial fibrous tissue content from 14.4 ± 1.8% (mean ± SEM) to 4.9 ± 1.2% (8 weeks after MI; P<0.05) versus Scr21 controls.
  
  
  CONCLUSIONS
  MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF.
authors.affiliation: Research Center, Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Cardin
authors.forename: Eduard
authors.initials: E
authors.lastname: Guasch
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Luo
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Khaï
authors.initials: K
authors.lastname: Le Quang
authors.forename: YanFen
authors.initials: Y
authors.lastname: Shi
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Philippe
authors.initials: P
authors.lastname: Comtois
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D016014:Linear Models; D008297:Male; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D020257:Ventricular Remodeling
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C404992:Spry2 protein, rat