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PERSPECTIVES |
1 Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Email: stefan.kaab{at}med.uni-muenchen.de
Variety and diversity as well as regional specificity of gene expression are the basis of normal cardiac function. Transcriptional regulation has been demonstrated to be an essential compensatory response to structural and functional changes in the heart. In order to understand transcriptional regulation in defined disease states it is essential to have a detailed knowledge of expression patterns in non-diseased myocardial tissue.
In this issue of The Journal of Physiology Gaborit et al. (2007) give a detailed analysis of differentially expressed ion channel genes controlling regional diversity of myocardial electrical properties in non-diseased human hearts. High-throughput real-time RT-PCR in a hypothesis driven approach allowed for a comprehensive description of 79 ion channels and related genes in specific regions of the human heart.
Differential expression of a variety of genes is giving clues to the molecular substrates controlling distinct myocardial electrical properties of specific regions in the heart and has been demonstrated in anatomically distinct regions of the heart such as atrial versus ventricular myocardium (Barth et al. 2005) or ventricular endocardium versus ventricular epicardium (Rosati et al. 2001). Genome wide expression studies in heart failure resulted in a description of deregulated gene clusters that can be attributed and sorted by functional groups such as metabolism, inflammation and signal transduction. While regional differences in deregulation of ion channels in normal and failing heart has been noted (Ellinghaus et al. 2005; Kääb et al. 2004), this study, in an unprecedented way, investigates a comprehensive set of ion channel genes and related genes in atria, ventricular epicardium and endocardium as well as in Purkinje fibres. The authors present and discuss their data in the context of previous findings and highlight novel findings of potential functional significance. Among the wealth of data, the detailed analysis of the Purkinje fibre system deserves special attention. The participation of Nav1.7 in TTX-sensitive Purkinje fibre INa, and the importance of low-level Na+,K+-ATPase and high-level inositol-trisphosphate receptor expression in the Purkinje system warrant further functional studies with respect to arrhythmogenesis. These data add to the discussion on Ca2+ signalling in the Purkinje system that was substantiated by the recent discovery of the molecular substrates of T- and L-type Ca2+ currents in Purkinje fibres in dog (Rosati et al. 2007).
In comparison to previous pan-genomic approaches on regional specific gene expression in the heart this quantitative RT-PCR based study allowed for the detection of low-abundance mRNAs and unmasked differences in expression levels to a greater extent than pan-genomic arrays (Kääb et al. 2004; Ellinghaus et al. 2005).
These data provide an important reference with a focus on low abundance ion channel genes for other studies aiming at:
genes exclusively expressed in atrial or ventricular tissue;
genes controlling electrical properties that may play an important functional role in arrhythmogenesis;
transcriptional deregulation contributing to a remodelling process in defined disease states in the human heart (e.g. hypertrophy, heart failure).
To link deregulation of ion channel genes to other potentially more global gene deregulation processes in the course of specific disease states more information especially on transcription factors involved will be needed.
More sophisticated and meticulous dissecting methods as well as a combination with functional studies have recently led to the detailed characterization of ion channel expression in rabbit atria and sinus node, linking the variety of gene expression on a microscopic level to specific electrical properties that guarantee physiological excitation and conduction (Tellez et al. 2006).
This holds out the promise that we will see a detailed analysis and understanding of the transcriptional control of key anatomical substrates of excitation and conduction such as sinus node, atrio-ventricular node, and crista terminalis in the human heart in the future.
References
Barth AS, Merk S, Arnoldi E, Zwermann L, Kloos P, Gebauer M, Steinmeyer K, Bleich M, Kääb S, Pfeufer A, Uberfuhr P, Dugas M, Steinbeck G & Nabauer M (2005). Pflugers Arch 450, 201–208.[CrossRef][Medline]
Ellinghaus P, Scheubel RJ, Dobrev D, Ravens U, Holtz J, Huetter J, Nielsch U & Morawietz H (2005). J Thorac Cardiovasc Surg 129, 1383–1390.
Gaborit N, LeBouter S, Szuts V, Varro A, Escande D, Nattel S & Demolombe S (2007). J Physiol 582, 675–693.
Kääb S, Barth AS, Margerie D, Dugas M, Gebauer M, Zwermann L, Merk S, Pfeufer A, Steinmeyer K, Bleich M, Kreuzer E, Steinbeck G & Nabauer M (2004). J Mol Med 82, 308–316.[CrossRef][Medline]
Rosati B, Dun W, Hirose M, Boyden PA & McKinnon D (2007). J Physiol 579, 465–471.
Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE & McKinnon D (2001). J Physiol 533, 119–125.
Tellez JO, Dobrzynski H, Greener ID, Graham GM, Laing E, Honjo H, Hubbard SJ, Boyett MR & Billeter R (2006). Circ Res 99, 1384–1393.
Related Article
J. Physiol. 2007 582: 675-693.
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