Contrasting gene expression profiles in two canine models of atrial fibrillation
Contrasting gene expression profiles in two canine models of atrial fibrillation
复制标题
DOI：
10.1161/01.res.0000258428.09589.1a
复制
发表时间：
2007-02-16
影响因子：
20.1
通讯作者：
Nattel, Stanley
中科院分区：
文献类型：
--
作者：
Cardin, Sophie;Libby, Eric;Nattel, Stanley
房颤患者基因表达的变化反映了潜在的心脏病底物和房颤诱导的房性心动过速重构的变化。这些在临床研究中很难分开。本研究评估了犬房速重构和充血性心力衰竭模型中时间依赖性mRNA表达的变化。5个实验组（5只犬/组）接受心房（ATP，400 bpm x 24小时，1周或6周）或心室（VTP，240 bpm x 24小时或2周）快速起搏。在分离的左心房心肌细胞中通过微阵列和（18个基因）通过实时RT-PCR分析了大约21，700个转录本的表达。蛋白质表达的变化进行了评估，通过蛋白质印迹。在VTP中，24小时（2209）和2周（2720）后均出现大量显著的mRNA表达变化。在ATP中，24小时（242）发生的变化较少，1周时更少（87），6周时无显著性变化。VTP表达的变化随时间以复杂的方式变化。细胞外基质相关的转录物被VTP强烈上调，与其病理生理学一致，其中8个胶原基因在2周（纤维化时间）上调> 10倍，胡萝卜素-1上调8倍，MMP 2上调4.5倍，但在24小时不变。其他细胞外基质基因（如纤连蛋白、赖氨酸氧化酶样2）在两个时间点均增加（分别约为10倍、约为5倍）。在ATP中，mRNA的变化几乎完全代表下调，并且在数量上较小。这项研究表明，VT诱导的充血性心力衰竭和ATP产生的基因表达变化的定性不同的时间演变模式，和特定的转录组反应与心房颤动与潜在的心脏病基板必须考虑在评估基因表达的变化在人。
Gene-expression changes in atrial fibrillation patients reflect both underlying heart-disease substrates and changes because of atrial fibrillation-induced atrial-tachycardia remodeling. These are difficult to separate in clinical investigations. This study assessed time-dependent mRNA expression-changes in canine models of atrial-tachycardia remodeling and congestive heart failure. Five experimental groups (5 dogs/group) were submitted to atrial (ATP, 400 bpm x 24 hours, 1 or 6 weeks) or ventricular (VTP, 240 bpm x 24 hours or 2 weeks) tachypacing. The expression of approximate to 21,700 transcripts was analyzed by microarray in isolated left-atrial cardiomyocytes and (for 18 genes) by real-time RT-PCR. Protein-expression changes were assessed by Western blot. In VTP, a large number of significant mRNA-expression changes occurred after both 24 hours (2209) and 2 weeks (2720). In ATP, fewer changes occurred at 24 hours (242) and fewer still (87) at 1 week, with no statistically-significant alterations at 6 weeks. Expression changes in VTP varied over time in complex ways. Extracellular matrix-related transcripts were strongly upregulated by VTP consistent with its pathophysiology, with 8 collagen-genes upregulated > 10-fold, fibrillin-1 8-fold and MMP2 4.5-fold at 2 weeks (time of fibrosis) but unchanged at 24 hours. Other extracellular matrix genes (eg, fibronectin, lysine oxidase-like 2) increased at both time-points (approximate to 10, approximate to 5-fold respectively). In ATP, mRNA-changes almost exclusively represented downregulation and were quantitatively smaller. This study shows that VTP-induced congestive heart failure and ATP produce qualitatively different temporally-evolving patterns of gene-expression change, and that specific transcriptomal responses associated with atrial fibrillation versus underlying heart disease substrates must be considered in assessing gene-expression changes in man.