Microarray Analysis Reveals Complex Remodeling of Cardiac Ion Channel Expression With Altered Thyroid Status: Relation to Cellular and Integrated Electrophysiology

• Published in: Circulation research Vol. 92; no. 2; pp. 234 - 242
• Main Authors: Bouter, Sabrina Le, Demolombe, Sophie, Chambellan, Arnaud, Bellocq, Chloé, Aimond, Franck, Toumaniantz, Gilles, Lande, Gilles, Siavoshian, Sepideh, Baró, Isabelle, Pond, Amber L, Nerbonne, Jeanne M, Léger, Jean J, Escande, Denis, Charpentier, Flavien
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 07.02.2003; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Animals; Biological and medical sciences; Body Weight; Electrocardiography; Electrophysiologic Techniques, Cardiac; Endocrinopathies; Gene Expression Profiling; Heart Rate - physiology; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Hyperthyroidism - physiopathology; Hypothyroidism - physiopathology; Ion Channels - biosynthesis; Ion Channels - genetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardium - chemistry; Myocardium - metabolism; Myocardium - pathology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Oligonucleotide Array Sequence Analysis; Organ Size; Patch-Clamp Techniques; Potassium Channels, Voltage-Gated - biosynthesis; Potassium Channels, Voltage-Gated - genetics; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; RNA, Messenger - metabolism; Thyroid. Thyroid axis (diseases); Endocrinopathy; Heart; Repolarization; Pathophysiology; Hyperthyroidism; Rodentia; Thyroid diseases; DNA chip; Electrophysiology; Action potential; cDNA microarray; Ionic channel; Gene expression; Hypothyroidism; Vertebrata; Mammalia; ionic remodeling; Complementary DNA; Mouse; ion channel; Animal; Circulatory system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000053185.75505.8E

ABSTRACT—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 Ito,f and IK,slow densities, and increased IKs density in hypothyroid myocytes. In addition to effects on K channel transcripts, transcripts for the pacemaker channel HCN2 were decreased and those encoding the α1C Ca 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 α- and β-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.