title: Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy.
abstract: OBJECTIVE
  Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM.
  
  
  RESULTS
  The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T(3)) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T(3) levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T(3) from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction.
  
  
  CONCLUSIONS
  Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Wang
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Cheng-Kun
authors.initials: CK
authors.lastname: Du
authors.forename: Qun-Wei
authors.initials: QW
authors.lastname: Lu
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Zhan
authors.forename: Takaki
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Yosikazu
authors.initials: Y
authors.lastname: Miwa
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000201:enzymology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011441:Propylthiouracil / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014158:Transcription, Genetic; D014284:Triiodothyronine / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D013956:Antithyroid Agents; D000242:Cyclic AMP; D007453:Iodide Peroxidase; D011441:Propylthiouracil; D051057:Proto-Oncogene Proteins c-akt; D014284:Triiodothyronine; D020107:Troponin T; D048051:p38 Mitogen-Activated Protein Kinases; D000097564:Iodothyronine Deiodinase Type II