Division of Experimental Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, P. O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Basic Res Cardiol. 2011 Nov;106(6):1269-81. doi: 10.1007/s00395-011-0229-1. Epub 2011 Nov 5.
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.
尽管左心室（LV）在心肌梗死后（MI）的重构似乎是合适的，但它是心力衰竭发展的独立危险因素。在大型动物物种中，关于 LV 重构的分子机制的研究很少。我们采用了一种无偏的分子方法来鉴定候选转录因子（TFs），这些转录因子介导 MI 后猪 LV 重构中涉及的遗传重编程。在 MI 诱导或假手术后 3 周，从远程非梗塞心肌中采集左心室组织。微阵列分析鉴定出 285 个上调和 278 个下调基因（FDR<0.05）。在这些差异表达的基因中，搜索了人类同源物的启动子区域，以寻找常见的 TF 结合位点（TFBS）。在上调基因和下调基因中，有 18 个 TFBS 被过度表达（p<0.01）超过两倍，有 13 个 TFBS 被过度表达（p<0.01）。通过蛋白/DNA 阵列分析，检测左心室核蛋白提取物的 DNA 结合活性。在 345 个 DNA 探针中，有 30 个显示信号强度变化超过两倍。在 TFBS 和蛋白/DNA 阵列分析中鉴定出 5 个 TF，只有 COUP-TFII 和糖皮质激素受体（GR）显示出匹配的变化。在 MI 后用 GR 拮抗剂米非司酮治疗猪，减少了 MI 后 LV 质量的增加，但 LV 扩张仍不受影响。因此，在生理相关的大型动物模型中，采用无偏方法研究 MI 后 LV 重构，我们鉴定出 COUP-TFII 和 GR 是 MI 后重构的潜在关键介质。
