title: Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure.
abstract: Alterations of cardiac gene expression are central to ventricular dysfunction in human heart failure (HF). The canine tachycardia pacing-induced HF model is known to reproduce the main hemodynamic, echocardiographic and electrophysiological changes observed in human HF. In this study, we use this HF model to compare gene expression profiles in the left and right ventricles (LV, RV) of normal and end-stage failing canine hearts and compare the transcription profiles to those in human and murine models of HF. In end-stage HF, the LV exhibits down regulation of genes involved in energy production, cardiac contraction, and modulation of excitation-contraction coupling as compared with normal LV. The majority of transcriptomic changes between normal and end-stage canine HF were shared by the RV and LV. Genes down regulated only in the LV included those involved in aerobic energy production pathways, regulation of actin filament length, and enzyme-linked receptor protein signaling pathways. In normal canine hearts, genes encoding specific components of the contractile apparatus exhibit LV-RV asymmetric expression patterns; in failing hearts, cardiac fetal transcription factors MEF2 and MITF and the stress-responsive transcription factor ATF4 showed interventricular differences in expression. The comparison among the canine tachypacing, mouse transgenic, and human HF reveals that human disease involves down regulation of genes in a broad range of biological processes while experimentally induced HF is associated with down regulation of energy pathways, and that human ischemic HF and canine HF share a similar over representation of transcriptional pathways in the up regulated genes. This study provides insights into the molecular pathways leading to end-stage tachycardia-induced HF, and into global transcriptomic differences between the animal HF models and human HF.
authors.affiliation: Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, MD 21218, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Gao
authors.forename: Hai
authors.initials: H
authors.lastname: Xu
authors.forename: Deborah
authors.initials: D
authors.lastname: DiSilvestre
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Halperin
authors.forename: Richard
authors.initials: R
authors.lastname: Tunin
authors.forename: Yanli
authors.initials: Y
authors.lastname: Tian
authors.forename: Wayne
authors.initials: W
authors.lastname: Yu
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D020869:Gene Expression Profiling / Q000379:methods; D006333:Heart Failure / Q000209:etiology / Q000235:genetics*; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis / Q000379:methods*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D012016:Reference Values; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013610:Tachycardia / Q000150:complications / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C497109:ATF4 protein, human; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D051701:Activating Transcription Factor 4