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(Circulation Research. 2003;92:234.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Microarray Analysis Reveals Complex Remodeling of Cardiac Ion Channel Expression With Altered Thyroid Status

Relation to Cellular and Integrated Electrophysiology

Sabrina Le Bouter^*, Sophie Demolombe^*, Arnaud Chambellan, Chloé Bellocq, Franck Aimond, Gilles Toumaniantz, Gilles Lande, Sepideh Siavoshian, Isabelle Baró, Amber L. Pond, Jeanne M. Nerbonne, Jean J. Léger, Denis Escande, Flavien Charpentier

From INSERM U533 (S.L.B., S.D., A.C., C.B., G.T., G.L., S.S., I.B., J.J.L., D.E., F.C.), Physiopathologie et Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine, Nantes, France; and the Department of Molecular Biology and Pharmacology (F.A., A.L.P., J.M.N.), Washington University School of Medicine, Saint-Louis, Mo.

Correspondence to Flavien Charpentier, PhD, INSERM U533, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes cedex, France. E-mail flavien.charpentier{at}nantes.inserm.fr

Although electrophysiological remodeling occurs in various myocardial diseases, the underlying molecular mechanisms are poorly understood. cDNA microarrays containing probes for a large population of mouse genes encoding ion channel subunits ("IonChips") were developed and exploited to investigate remodeling of ion channel transcripts associated with altered thyroid status in adult mouse ventricle. Functional consequences of hypo- and hyperthyroidism were evaluated with patch-clamp and ECG recordings. Hypothyroidism decreased heart rate and prolonged QTc duration. Opposite changes were observed in hyperthyroidism. Microarray analysis revealed that hypothyroidism induces significant reductions in KCNA5, KCNB1, KCND2, and KCNK2 transcripts, whereas KCNQ1 and KCNE1 expression is increased. In hyperthyroidism, in contrast, KCNA5 and KCNB1 expression is increased and KCNQ1 and KCNE1 expression is decreased. Real-time RT-PCR validated these results. Consistent with microarray analysis, Western blot experiments confirmed those modifications at the protein level. Patch-clamp recordings revealed significant reductions in I_to,f and I_K,slow densities, and increased I_Ks density in hypothyroid myocytes. In addition to effects on K⁺ channel transcripts, transcripts for the pacemaker channel HCN2 were decreased and those encoding the 1C Ca²⁺ channel (CaCNA1C) were increased in hypothyroid animals. The expression of Na⁺, Cl^-, and inwardly rectifying K⁺ channel subunits, in contrast, were unaffected by thyroid hormone status. Taken together, these data demonstrate that thyroid hormone levels selectively and differentially regulate transcript expression for at least nine ion channel - and ß-subunits. Our results also document the potential of cDNA microarray analysis for the simultaneous examination of ion channel transcript expression levels in the diseased/remodeled myocardium.

Key Words: ion channel • cDNA microarray • repolarization • ionic remodeling

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