| Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy. | |
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MedLine Citation:
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PMID: 20453157 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIMS: 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. METHODS AND 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. CONCLUSION: Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM. |
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Authors:
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Yuan-Yuan Wang; Sachio Morimoto; Cheng-Kun Du; Qun-Wei Lu; Dong-Yun Zhan; Takaki Tsutsumi; Tomomi Ide; Yosikazu Miwa; Fumi Takahashi-Yanaga; Toshiyuki Sasaguri |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-07 |
Journal Detail:
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Title: Cardiovascular research Volume: 87 ISSN: 1755-3245 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-13 Completed Date: 2010-12-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: England |
Other Details:
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Languages: eng Pagination: 636-46 Citation Subset: IM |
Affiliation:
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Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antithyroid Agents / pharmacology Cardiomyopathy, Dilated / drug therapy, enzymology*, genetics, physiopathology Cells, Cultured Cyclic AMP / metabolism Disease Models, Animal Female Gene Expression Profiling Gene Expression Regulation, Enzymologic Iodide Peroxidase / genetics, metabolism* Male Mice Mice, Inbred C57BL Mice, Transgenic Mutation Myocardium / enzymology* Oligonucleotide Array Sequence Analysis Phosphorylation Propylthiouracil / pharmacology Proto-Oncogene Proteins c-akt / metabolism Transcription, Genetic Triiodothyronine / metabolism Troponin T / genetics, metabolism Up-Regulation Ventricular Remodeling* / drug effects p38 Mitogen-Activated Protein Kinases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antithyroid Agents; 0/Troponin T; 51-52-5/Propylthiouracil; 60-92-4/Cyclic AMP; 6893-02-3/Triiodothyronine; EC 1.11.1.-/iodothyronine deiodinase type II; EC 1.11.1.8/Iodide Peroxidase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
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