Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation
Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation
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DOI：
10.1161/circulationaha.104.506857
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发表时间：
2005-07-26
期刊：
影响因子：
37.8
通讯作者：
Demolombe, S
中科院分区：
文献类型：
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作者：
Gaborit, N;Steenman, M;Demolombe, S
背景-瓣膜性心脏病（VHD）常导致心房颤动（AF），而AF均引起离子通道重构。我们评估了患有永久性房颤（AF-VHD）或窦性心律（SR-VHD）的VHD患者的离子通道基因表达谱，并与非房颤或VHD患者进行了比较，方法和结果-我们使用含有人类离子通道和Ca 2+调节基因探针的微阵列来定量7名SR-VHD患者和11名AF患者心房组织中的mRNA表达。VHD患者相对于11例无结构性心脏病的SR（SR-CAD）对照患者。从数据集中，我们选择了59个在人类心脏中表达的转录本进行详细分析。SR-VHD患者差异表达24/59离子通道和Ca 2+调节因子转录本。VHD组之间存在显着重叠，SR-VHD患者中66%的基因改变在AF-VHD中也发生了类似的改变。AF和SR-VHD组之间的统计学差异确定了AF的特定分子画像，其中涉及12个基因，这些基因通过实时逆转录聚合酶链反应进一步证实。例如，与SR-VHD相比，受磷蛋白、β亚基MinK（KCNE 1）和MIRP 2（KCNE 3）以及2孔钾通道TWIK-1在AF- VHD中上调，而T型钙通道Cav3.1和瞬时外向钾通道Kv4.3下调。双向分层聚类将SR-VHD与AF-VHD患者分开。在蛋白质和功能水平证实了L型钙电流和内向整流电流的AF相关变化。最后，对于13个选定的基因，SR恢复逆转离子通道remodeling.Conclusions - VHD广泛重塑心脏离子通道和转运蛋白的表达，AF改变离子通道的表达在VHD患者。
Background - Valvular heart disease (VHD), which often leads to atrial fibrillation (AF), and AF both cause ion-channel remodeling. We evaluated the ion-channel gene expression profile of VHD patients, in permanent AF (AF-VHD) or in sinus rhythm (SR-VHD), in comparison with patients without AF or VHD, respectively.Methods and Results - We used microarrays containing probes for human ion-channel and Ca2+-regulator genes to quantify mRNA expression in atrial tissues from 7 SR-VHD patients and 11 AF-VHD patients relative to 11 control patients in SR without structural heart disease (SR-CAD). From the data set, we selected for detailed analysis 59 transcripts expressed in the human heart. SR-VHD patients differentially expressed 24/59 ion-channel and Ca2+-regulator transcripts. There was significant overlap between VHD groups, with 66% of genes altered in SR-VHD patients being similarly modified in AF-VHD. Statistical differences between the AF- and SR-VHD groups identified the specific molecular portrait of AF, which involved 12 genes that were further confirmed by real-time reverse transcription-polymerase chain reaction. For example, phospholamban, the beta-subunit MinK (KCNE1) and MIRP2 (KCNE3), and the 2-pore potassium channel TWIK-1 were upregulated in AF- VHD compared with SR-VHD, whereas the T-type calcium-channel Cav3.1 and the transient-outward potassium channel Kv4.3 were downregulated. Two-way hierarchical clustering separated SR-VHD from AF- VHD patients. AF- related changes in L-type Ca2+-current and inward-rectifier current were confirmed at protein and functional levels. Finally, for 13 selected genes, SR restoration reversed ion-channel remodeling.Conclusions - VHD extensively remodels cardiac ion-channel and transporter expression, and AF alters ion-channel expression in VHD patients.