Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart
Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart
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DOI：
10.1113/jphysiol.2006.126714
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发表时间：
2007-07-15
影响因子：
5.5
通讯作者：
Demolombe, Sophie
中科院分区：
文献类型：
--
作者：
Gaborit, Nathalie;Le Bouter, Sabrina;Demolombe, Sophie
由于离子通道功能表达的特定模式，不同的心脏区域具有与其电专门化相适应的特定动作电位属性。本研究用基因组学的方法研究了非病变心脏中不同区域离子通道的表达。采用高通量实时荧光定量RT-PCR技术，对15例正常人心脏组织中79个离子通道亚单位转录本及其相关基因在心房、心外膜、心内膜和浦肯野纤维中的表达模式进行了定量研究。双向非定向等级聚类分离了心房、浦肯野纤维和室间隔，但没有显示心外膜和心内膜的特定模式，也没有显示左和右室的特定模式。与预期的一样，以心房和心室为特征的基因包括Cx40、Kv1.5和Kir3.1，但也包括Cav1.3、Cav3.1、Cav Alpha 2 Delta 2、Nav beta 1、TWIK1、TASK1和HCN4。只有Kir2.1、RyR2、磷蛋白和Kv1.4在脑室有较高的表达。Purkinje纤维表达画像(相对于脑室)包括Cx40、Kv4.3、Kir3.1、TWIK1、HCN4、ClC6和CALM1的强表达，而编码Cx43、Kir2.1、KChIP2、泵/交换器Na+、K+-ATPase、NCX1、SERCA2和钙处理蛋白RYR2和CASQ2的mRNA表达较弱。在心外膜(相对于心内膜)表达更强的转录本包括Cav1.2、KChIP2、SERCA2、CALM3和钙调神经磷酸酶-α。NaV1.5和Navβ1在心内膜中表达较强。对于选定的基因，RT-PCR数据在蛋白质水平得到了证实。这是全球首次报道未患病的人心脏中区域离子通道亚单位基因的表达。我们的数据指出了显著的区域决定的离子通道表达差异，对于理解区域电生理学、心律失常机制和对离子通道阻断药物的反应具有潜在的重要意义。与以往的功能研究一致，提示心肌离子电流表达的区域调控可能主要是转录调控。
The various cardiac regions have specific action potential properties appropriate to their electrical specialization, resulting from a specific pattern of ion-channel functional expression. The present study addressed regionally defined differential ion-channel expression in the non-diseased human heart with a genomic approach. High-throughput real-time RT-PCR was used to quantify the expression patterns of 79 ion-channel subunit transcripts and related genes in atria, ventricular epicardium and endocardium, and Purkinje fibres isolated from 15 non-diseased human donor hearts. Two-way non-directed hierarchical clustering separated atria, Purkinje fibre and ventricular compartments, but did not show specific patterns for epicardium versus endocardium, nor left- versus right-sided chambers. Genes that characterized the atria (versus ventricles) included Cx40, Kv1.5 and Kir3.1 as expected, but also Cav1.3, Cav3.1, Cav alpha 2 delta 2, Nav beta 1, TWIK1, TASK1 and HCN4. Only Kir2.1, RyR2, phospholamban and Kv1.4 showed higher expression in the ventricles. The Purkinje fibre expression-portrait (versus ventricle) included stronger expression of Cx40, Kv4.3, Kir3.1, TWIK1, HCN4, ClC6 and CALM1, along with weaker expression of mRNA encoding Cx43, Kir2.1, KChIP2, the pumps/exchangers Na+,K+-ATPase, NCX1, SERCA2, and the Ca2+-handling proteins RYR2 and CASQ2. Transcripts that were more strongly expressed in epicardium (versus endocardium) included Cav1.2, KChIP2, SERCA2, CALM3 and calcineurin-alpha. Nav1.5 and Nav beta 1 were more strongly expressed in the endocardium. For selected genes, RT-PCR data were confirmed at the protein level. This is the first report of the global portrait of regional ion-channel subunit-gene expression in the non-diseased human heart. Our data point to significant regionally determined ion-channel expression differences, with potentially important implications for understanding regional electrophysiology, arrhythmia mechanisms, and responses to ion-channel blocking drugs. Concordance with previous functional studies suggests that regional regulation of cardiac ion-current expression may be primarily transcriptional.