Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach

Abstract

Despite the apparent appropriateness of left ventricular (LV) remodeling following myocardial infarction (MI), it poses an independent risk factor for development of heart failure. There is a paucity of studies into the molecular mechanisms of LV remodeling in large animal species. We took an unbiased molecular approach to identify candidate transcription factors (TFs) mediating the genetic reprogramming involved in post-MI LV remodeling in swine. Left ventricular tissue was collected from remote, non-infarcted myocardium, 3 weeks after MI-induction or sham-surgery. Microarray analysis identified 285 upregulated and 278 downregulated genes (FDR < 0.05). Of these differentially expressed genes, the promoter regions of the human homologs were searched for common TF binding sites (TFBS). Eighteen TFBS were overrepresented >two-fold (p < 0.01) in upregulated and 13 in downregulated genes. Left ventricular nuclear protein extracts were assayed for DNA-binding activity by protein/DNA array. Out of 345 DNA probes, 30 showed signal intensity changes >two-fold. Five TFs were identified in both TFBS and protein/DNA array analyses, which showed matching changes for COUP-TFII and glucocorticoid receptor (GR) only. Treatment of swine with the GR antagonist mifepristone after MI reduced the post-MI increase in LV mass, but LV dilation remained unaffected. Thus, using an unbiased approach to study post-MI LV remodeling in a physiologically relevant large animal model, we identified COUP-TFII and GR as potential key mediators of post-MI remodeling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-011-0229-1) contains supplementary material, which is available to authorized users.

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

“…16,17 2D ejection fraction was calculated as (EDA − ESA)/EDA × 100%. Also, blood samples were taken from the aorta and collected in EDTA anticoagulation tubes, centrifuged, and plasma was stored at − 80°C until further analysis.…”

Gene reprogramming in exercise-induced cardiac hypertrophy in swine: A transcriptional genomics approach

“…Extracts from four animals per group were pooled and then semi-quantitatively assayed for DNA binding activity to a protein/ DNA array (Combo array, Panomics/Affymetrix, Milan, Italy) containing 345 distinct DNA probes [19]. TF binding activity was considered significant when there was at least a 2-fold signal difference between both nuclear protein pools.…”

“…RNA isolation and subsequent microarray analysis was performed for eight exercise-trained animals and for eight sedentary animals (four females and four males in each group) as described elsewhere [19]. Microarray analysis was performed using GeneChip Porcine Genome Arrays (Affymetrix, Santa Clara, CA, USA).…”

“…Of the human homologues of the differentially expressed (DE) genes, regions between 500 bp upstream and 100 bp downstream of the transcription start site were scanned for the presence of putative TF binding sites (TFBSs), as described [19]. Overrepresentation of TFBS in the up-and downregulated genes was determined using a onetailed Fisher exact probability test and considered significant when more than 1.5-fold and at P b 0.01.…”

“…We have previously reported on the changes in gene expression profiles, and implicated transcription factors, that underlie hypertrophy of the left ventricle (LV) during recovery from a MI [19]. Here, we studied the molecular pathways that underlie physiological hypertrophy and the TFs that drive these changes in LV hypertrophy caused by 3-6 weeks of dynamic exercise-training in swine.…”