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

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 unbias...

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Autores principales: Kuster, Diederik W. D., Merkus, Daphne, Kremer, Andreas, van IJcken, Wilfred F. J., de Beer, Vincent J., Verhoeven, Adrie J. M., Duncker, Dirk J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer-Verlag 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228945/
https://www.ncbi.nlm.nih.gov/pubmed/22057716
http://dx.doi.org/10.1007/s00395-011-0229-1
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author Kuster, Diederik W. D.
Merkus, Daphne
Kremer, Andreas
van IJcken, Wilfred F. J.
de Beer, Vincent J.
Verhoeven, Adrie J. M.
Duncker, Dirk J.
author_facet Kuster, Diederik W. D.
Merkus, Daphne
Kremer, Andreas
van IJcken, Wilfred F. J.
de Beer, Vincent J.
Verhoeven, Adrie J. M.
Duncker, Dirk J.
author_sort Kuster, Diederik W. D.
collection PubMed
description 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 MATERIAL: The online version of this article (doi:10.1007/s00395-011-0229-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-32289452011-12-27 Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach Kuster, Diederik W. D. Merkus, Daphne Kremer, Andreas van IJcken, Wilfred F. J. de Beer, Vincent J. Verhoeven, Adrie J. M. Duncker, Dirk J. Basic Res Cardiol Original Contribution 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 MATERIAL: The online version of this article (doi:10.1007/s00395-011-0229-1) contains supplementary material, which is available to authorized users. Springer-Verlag 2011-11-05 2011 /pmc/articles/PMC3228945/ /pubmed/22057716 http://dx.doi.org/10.1007/s00395-011-0229-1 Text en © The Author(s) 2011 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Original Contribution
Kuster, Diederik W. D.
Merkus, Daphne
Kremer, Andreas
van IJcken, Wilfred F. J.
de Beer, Vincent J.
Verhoeven, Adrie J. M.
Duncker, Dirk J.
Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
title Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
title_full Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
title_fullStr Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
title_full_unstemmed Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
title_short Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
title_sort left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach
topic Original Contribution
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228945/
https://www.ncbi.nlm.nih.gov/pubmed/22057716
http://dx.doi.org/10.1007/s00395-011-0229-1
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