title: Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines.
abstract: OBJECTIVE
  The present study was designed to decipher molecular mechanisms underlying nicotine's promoting atrial fibrillation (AF) by inducing atrial structural remodelling.
  
  
  RESULTS
  The canine model of AF was successfully established by nicotine administration and rapid pacing. The atrial fibroblasts isolated from healthy dogs were treated with nicotine. The role of microRNAs (miRNAs) on the expression and regulation of transforming growth factor-beta1 (TGF-beta1), TGF-beta receptor type II (TGF-betaRII), and collagen production was evaluated in vivo and in vitro. Administration of nicotine for 30 days increased AF vulnerability by approximately eight- to 15-fold in dogs. Nicotine stimulated remarkable collagen production and atrial fibrosis both in vitro in cultured canine atrial fibroblasts and in vivo in atrial tissues. Nicotine produced significant upregulation of expression of TGF-beta1 and TGF-betaRII at the protein level, and a 60-70% decrease in the levels of miRNAs miR-133 and miR-590. This downregulation of miR-133 and miR-590 partly accounts for the upregulation of TGF-beta1 and TGF-betaRII, because our data established TGF-beta1 and TGF-betaRII as targets for miR-133 and miR-590 repression. Transfection of miR-133 or miR-590 into cultured atrial fibroblasts decreased TGF-beta1 and TGF-betaRII levels and collagen content. These effects were abolished by the antisense oligonucleotides against miR-133 or miR-590. The effects of nicotine were prevented by an alpha7 nicotinic acetylcholine receptor antagonist.
  
  
  CONCLUSIONS
  We conclude that the profibrotic response to nicotine in canine atrium is critically dependent upon downregulation of miR-133 and miR-590.
authors.affiliation: Department of Pharmacology, State-Province Key Laboratories of Biomedicine and Pharmaceutics, Harbin, Heilongjiang 150081, PR China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Shan
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.forename: Benzhi
authors.initials: B
authors.lastname: Cai
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Xuelian
authors.initials: X
authors.lastname: Li
authors.forename: Tieming
authors.initials: T
authors.lastname: Feng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002304:Cardiac Pacing, Artificial; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009538:Nicotine; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D035683:MicroRNAs; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II