title: Detailed characterization of microRNA changes in a canine heart failure model: Relationship to arrhythmogenic structural remodeling.
abstract: Heart failure (HF) causes left-atrial (LA) and left-ventricular (LV) remodeling, with particularly-prominent changes in LA that create a substrate for atrial fibrillation (AF). MicroRNAs (miRs) are potential regulators in cardiac remodeling. This study evaluated time-dependent miR expression-changes in LA and LV tissue, fibroblasts and cardiomyocytes in experimental HF. HF was induced in dogs by ventricular tachypacing (varying periods, up to 2weeks). Following screening-microarray, 15 miRs were selected for detailed real-time qPCR assay. Extracellular matrix mRNA-expression was assessed by qPCR. Tachypacing time-dependently reduced LV ejection-fraction, increased LV-volume and AF-duration, and caused tissue-fibrosis with LA changes greater than LV. Tissue miR-expression significantly changed in LA for 10 miRs; in LV for none. Cell-selective analysis showed significant time-dependent changes in LA-fibroblasts for 10/15 miRs, LV-fibroblasts 8/15, LA-cardiomyocytes in 6/15 and LV-cardiomyocytes 3/15. Cell-expression specificity did not predict cell-specificity of VTP-induced expression-changes, e.g. 4/6 cardiomyocyte-selective miRs changed almost exclusively in fibroblasts (miR-1, miR-208b, miR133a/b). Thirteen miRs directly implicated in fibrosis/extracellular-matrix regulation were prominently changed: 9/13 showed fibroblast-selective alterations and 5/13 LA-selective. Multiple miRs changed in relation to associated extracellular-matrix targets. Experimental HF causes tissue and cell-type selective, time-dependent changes in cardiac miR-expression. Expression-changes are greater in LA versus LV, and greater in fibroblasts than cardiomyocytes, even for most cardiomyocyte-enriched miRs. This study, the first to examine time, chamber and cell-type selective changes in an experimental model of HF, suggests that multiple miR-changes underlie the atrial-selective fibrotic response and emphasize the importance of considering cell-specificity of miR expression-changes in cardiac remodeling paradigms.
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Ludwig-Maximilians University, Munich, Department of Medicine I, Klinikum Grosshadern, Germany.
authors.forename: Reza
authors.initials: R
authors.lastname: Wakili
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jiening
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University Tao-Yuan, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Ludwig-Maximilians University, Munich, Department of Medicine I, Klinikum Grosshadern, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Clauss
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Kristin
authors.initials: K
authors.lastname: Dawson
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Shi
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.affiliation: Ludwig-Maximilians University, Munich, Department of Medicine I, Klinikum Grosshadern, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada. Electronic address: stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D004285:Dogs; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006325:Heart Atria / Q000473:pathology; D006333:Heart Failure / Q000378:metabolism*; D006352:Heart Ventricles / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009928:Organ Specificity; D059467:Transcriptome; D020257:Ventricular Remodeling
chemical_list: D024042:Collagen Type I; D035683:MicroRNAs
keywords: Fibrosis; Heart failure; MicroRNA; Remodeling