title: Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism.
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.
authors.affiliation: First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Fu-Shin Road no 5, Kwei-Shan, Tao-Yuan, Taiwan. wjchen@adm.cgmh.org.tw
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Kuo
mesh_terms: D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006980:Hyperthyroidism / Q000150:complications / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D015398:Signal Transduction; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D003094:Collagen; D002118:Calcium