Up-regulation of type 2 iodothyronine deiodinase in dilated cardiomyopathy

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

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

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 ΔK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T3) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T3 levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T3 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.

Original languageEnglish
Pages (from-to)636-646
Number of pages11
JournalCardiovascular research
Volume87
Issue number4
DOIs
Publication statusPublished - Sep 1 2010

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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