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Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism

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Abstract

Atrial fibrillation (AF) is a common complication in hyperthyroidism. Earlier studies demonstrate that thyroid hormone decreases L-type calcium channel (LCC) current expression with resultant shortening of action potential duration (APD), providing a substrate for AF. The aim of this study was to investigate the potential mechanism underlying the regulatory effect of thyroid hormone on LCC. In a hyperthyroid rat model, thyroid hormone (triiodothyronine [T3]) administration down-regulated atrial LCC expression. In vitro, treatment of murine atrial myocytes (HL-1) with T3 decreased the expression of LCC and its current, resulting in abbreviation of APD. Furthermore, T3 inhibited the activation of cyclic AMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Transient transfection studies in HL-1 cells indicated that T3 reduced LCC promoter activity. Deletion and mutation analysis of the LCC promoter region along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE was essential for T3-mediated LCC gene expression. Transfection of dominant-negative CREB (mutated Ser133) and mutant thyroid hormone receptor (TR, mutated Cys51) abolished the T3-dependent effects, suggesting an association between both transcriptional factors. Co-immunoprecipitation documented an increased binding of TR with CREB after T3 treatment. The transcriptional cross-talk 3 between TR and CREB bound to CRE mediates T3-inhibited CREB activity and LCC expression. Thyroid hormone-induced TR binding of CREB inhibits CREB activity and LCC current expression, which may contribute to AF. These findings provide an important mechanistic insight into hyperthyroidism-induced AF.

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Acknowledgments

This work was supported by grants from the Chang Gung Research Grant Foundation [G32102 and G331023] and National Science Council Grants [NSC-94-2314-B-182A-198]. We thank Mr. Chih-Chun Chen for his technical assistance in confocal microscope.

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Authors and Affiliations

  1. First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Fu-Shin Road no 5, Kwei-Shan, Tao-Yuan, Taiwan

    Wei-Jan Chen, Yung-Hsin Yeh & Chi-Tai Kuo

  2. Department of Biochemistry, Chang Gung University, Tao-Yuan, Taiwan

    Kwang-Huei Lin

  3. Graduate Institute of Clinical Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan

    Gwo-Jyh Chang

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  1. Wei-Jan Chen
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Correspondence to Wei-Jan Chen.

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W.-J. Chen and Y.-H. Yeh contributed equally to this work.

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Chen, WJ., Yeh, YH., Lin, KH. et al. Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism. Basic Res Cardiol 106, 163–174 (2011). https://doi.org/10.1007/s00395-010-0149-5

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