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 enzymelinked 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.

The enigmatic role of the ankyrin repeat domain 1 gene in heart development and disease

“…In this sense, the reduced expression of both ankrd1 (Zou et al, 1997) and mlc2v (Lyons et al, 1995) in a Nkx2.5-deficient background does not correlate well with the demonstration that ANKRD1/CARP inhibits the mlc2v reporter gene activity in vitro. Moreover, mlc2v was not identified as the gene downregulated in the LV myocardium of MLP-deficient mice (Gao et al, 2006), and no decreased levels of MLC2v and TNNC were detected in MLP -/-hearts characterized by very high levels of ankrd1 expression as compared to controls . In patients, end-stage DCM is associated with a marked activation of the ankrd1 (see Table 2) and selective upregulation (not inhibition) of the mlc2v gene in failing as compared to non-failing LV myocardium (Haase et al, 2002).…”

Altered expression of a limited number of genes contributes to cardiac decompensation during chronic ventricular tachypacing in dogs

“…The present study meets in part those criteria. A microarray analysis on cardiac tissue from dogs with pacing-induced heart failure was performed by Gao et al (7). By employing a less specific human 20K cDNA microarray and by using also existing databases, they compared gene expression profiles of normal and end-stage failing canine hearts as well as human and murine models of heart failure.…”

Differential Behaviors of Atrial Versus Ventricular Fibroblasts

“…Cardiac chamber-specific gene expression patterns exist throughout development 17 diseased 21,22 myocardium. Cardiac overexpression of junctin, an integral membrane protein colocalizing with ryanodine receptors and calsequestrin, causes markedly enlarged, severely fibrotic atria with much more limited ventricular fibrosis.…”