Expression profiling of cardiac genes in Tako-Tsubo cardiomyopathy:: Insight into a new cardiac entity
Expression profiling of cardiac genes in Tako-Tsubo cardiomyopathy:: Insight into a new cardiac entity
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DOI：
10.1016/j.yjmcc.2007.10.015
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发表时间：
2008-02-01
影响因子：
5
通讯作者：
Elsaesser, Albrecht
中科院分区：
文献类型：
--
作者：
Nef, Holger M.;Moellmann, Helge;Elsaesser, Albrecht
Tako-Tsubo心肌病(TTC)以一过性收缩功能障碍为特征，但其具体的发病机制尚不清楚。因此，我们通过微阵列分析对急性期和功能恢复后的基因进行了系统的表达谱分析。我们研究了3名女性TTC患者。从急性期(A组)和功能恢复后(13组)的左心室活检组织中提取互补RNA。利用基因芯片对其进行基因表达谱分析。用基因集丰富分析(GSEA)生物信息学工具确定功能相关基因。通过实时荧光定量聚合酶链式反应和免疫组织化学的方法对所选基因进行验证。在A组中，不同的功能基因集，如Nrf2诱导的基因，由氧化应激触发，以及蛋白质生物合成，在上调的靶基因中显著过度表达。RT-PCR证实GPX1、CAT、RPS6和eIF4E的转录增加。两组Akt/PKB信号转导靶点均明显上调。免疫组织化学显示，下游靶标核因子-kappaB和bclX-L上调并激活。参与能量代谢(氧化磷酸化、线粒体基因)的基因集在A组中没有差异，但在B组中过度表达。本研究表明氧化应激在TTC的发病机制中具有重要作用；它可能是由过量的儿茶酚胺触发的。蛋白质生物合成增加和激活的细胞存活级联可被解释为潜在的代偿机制。在功能恢复后，参与能量代谢的过程发挥了关键作用，从而可能有助于收缩功能的正常化。(C)2007 Elsevier Inc.保留所有权利。
Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction, but its specific pathomechanism remains unknown. Thus, we performed a systematic expression profiling of genes by microarray analysis in the acute phase and after functional recovery. We studied 3 female patients presenting with TTC. Complementary RNA was isolated from left ventricular biopsies taken in the acute phase (group A) and after functional recovery (group 13). It was profiled for gene expression using cDNA microarrays. Functionally related genes were determined with the Gene Set Enrichment Analysis (GSEA) bioinformatic tool. Validation of selected genes was performed by means of real-time PCR and immunohistochemistry. In group A, different functional gene sets, such as Nrf2-induced genes, triggered by oxidative stress, and protein biosynthesis were significantly overrepresented among the upregulated targets. Increased transcription of GPX1, CAT, RPS6, and eIF4E was confirmed by RT-PCR. The targets of the Akt/PKB signaling showed significant upregulation in both groups. Immumohistochemistry showed that the downstream targets NF-kappa B and BcL-X-L are upregulated and activated. Gene sets involved in energy metabolism (oxidative phosphorylation, mitochondrial genes) showed no differences in group A but were overexpressed in group B. This study demonstrated a significant contribution of oxidative stress to the pathomechanism of TTC; it is possibly triggered by excess catecholarnine. Increased protein biosynthesis and an activated cell survival cascade can be interpreted as potential compensatory mechanisms. After functional recovery, processes involved in energy metabolism play a pivotal role, thereby potentially contributing to the normalization of contractile function. (c) 2007 Elsevier Inc. All rights reserved.