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CARDIOVASCULAR |
1 INSERM, U533, Nantes, F-4400 France
2 Université de Nantes, faculté de Médecine, Nantes, F-4400 France
3 Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
4 Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
5 Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary
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
2
2, Nav
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-. Nav1.5 and Nav1 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.
(Received 15 December 2006;
accepted after revision 2 May 2007;
first published online 3 May 2007)
Corresponding author S. Demolombe: L'institut du thorax, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes cedex, France. Email: sophie.demolombe{at}nantes.inserm.fr
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J. Physiol. 2007 582: 473.
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