title: Long-term amiodarone treatment causes cardioselective hypothyroid-like alteration in gene expression profile.
abstract: The long-term cardiac effects of amiodarone resemble many aspects of hypothyroidism. The anti-arrhythmic potential of amiodarone may therefore be the result of a drug-induced, local hypothyroid-like condition. To investigate this controversial issue, we compared gene expression profiles in the hearts of rats treated with amiodarone with those of rats with hypothyroidism. Wistar male rats were assigned to 3 groups (n=6-8): Control, systemic hypothyroidism (hypothyroidism) and amiodarone treatment (amiodarone, 150 mg/kg/day, p.o., 4 weeks). Electrocardiogram (ECG) recordings, gene profiling by DNA microarray and Northern blotting were carried out. Amiodarone, like hypothyroidism, caused significant prolongation of RR and QT intervals in ECGs. Microarray analysis of 8435 genes in the left ventricular myocardium revealed a significant similarity in expression profiles between hypothyroidism and amiodarone (R=0.63, p<0.00001). The gene expression profiles of hypothyroidism and amiodarone showed closer correlation when top 100 up-regulated and 100 down-regulated genes in hypothyroidism (total 200 genes) were analyzed (R=0.78, p<0.00001). Northern blots of left ventricular myocardium showed a parallel decrease in mRNAs for myosin heavy chain (MHC)-alpha and a parallel increase for myosin heavy chain (MHC)-beta in hypothyroidism and amiodarone. In the liver and pituitary, in contrast, Northern blots showed quite different changes in the transcripts of the representative T3-responsive genes in the hypothyroidism and amiodarone. In conclusion, long-term treatment with amiodarone causes cardioselective hypothyroid-like alterations in gene expression profiles. The potent anti-arrhythmic activity of amiodarone may be attributable, in part at least, to this unique transcriptional remodeling.
authors.affiliation: Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Rong-qian
authors.initials: RQ
authors.lastname: Shi
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Fukushi
authors.initials: F
authors.lastname: Kambe
authors.forename: Sugiko
authors.initials: S
authors.lastname: Futaki
authors.forename: Hisao
authors.initials: H
authors.lastname: Seo
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004562:Electrocardiography; D020869:Gene Expression Profiling / Q000379:methods; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007037:Hypothyroidism / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008713:Methimazole; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D012333:RNA, Messenger; D008713:Methimazole; D000638:Amiodarone