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Basic Research in Cardiology

, Volume 106, Issue 6, pp 1269–1281

First Online: 05 November 2011Received: 30 August 2011Revised: 04 October 2011Accepted: 20 October 2011

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.

KeywordsHypertrophy Myocardial infarction Transcription factors Microarray Animal models of human diseases Systolic dysfunction Electronic supplementary materialThe 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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Author: Diederik W. D. Kuster - Daphne Merkus - Andreas Kremer - Wilfred F. J. van IJcken - Vincent J. de Beer - Adrie J. M.

Source: https://link.springer.com/







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