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Cardiovascular Research Advance Access first published online on April 27, 2009
This version [Corrected Proof] published online on May 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp130
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines

Hongli Shan1,{dagger}, Yong Zhang1,{dagger}, Yanjie Lu2,{dagger}, Ying Zhang1, Zhenwei Pan1, Benzhi Cai1, Ning Wang1, Xuelian Li1, Tieming Feng1, Yuan Hong1 and Baofeng Yang1,2,*

1 Department of Pharmacology, State-Province Key Laboratories of Biomedicine and Pharmaceutics, Harbin, Heilongjiang 150081, PR China
2 Cardiovascular Research Institute, Harbin Medical University, Harbin, Heilongjiang 150081, PR China

* Corresponding author. Tel: +86 451 86671354; fax: +86 451 86675769. E-mail address: yangbf{at}ems.hrbmu.edu.cn

Aims: The present study was designed to decipher molecular mechanisms underlying nicotine's promoting atrial fibrillation (AF) by inducing atrial structural remodelling.

Methods and 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-β1 (TGF-β1), TGF-β receptor type II (TGF-βRII), and collagen production was evaluated in vivo and in vitro. Administration of nicotine for 30 days increased AF vulnerability by ~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-β1 and TGF-βRII 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-β1 and TGF-βRII, because our data established TGF-β1 and TGF-βRII as targets for miR-133 and miR-590 repression. Transfection of miR-133 or miR-590 into cultured atrial fibroblasts decreased TGF-β1 and TGF-βRII 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 {alpha}7 nicotinic acetylcholine receptor antagonist.

Conclusion: We conclude that the profibrotic response to nicotine in canine atrium is critically dependent upon downregulation of miR-133 and miR-590.

KEYWORDS Nicotine; Atrial fibrosis; MiR-133; MiR-590

Time for primary review: 29 days

{dagger} The first three authors contributed equally to this work.


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