Signaling pathways responsible for fetal gene induction in the failing human heart: Evidence for altered thyroid hormone receptor gene expression

Koichiro Kinugawa, Wayne A. Minobe, William M. Wood, E. Chester Ridgway, John D. Baxter, Ralff C.J. Ribeiro, Magdy F. Tawadrous, Brian A. Lowes, Carlin S. Long, Michael R. Bristow

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

Background - We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs). Methods and Results - To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie. decreased expression of α-MHC with increased β-MHC expression compared with left ventricles from age-matched controls. We detected expression of TR-α1, -α2, and -β1 isoforms in human left ventricles. In failing left ventricles, TR-α1 was downregulated, whereas TR-α2, a splice variant that does not bind thyroid hormone but inhibits responses to liganded TRs, was increased. Expression levels of TR-β1 did not differ significantly between the 2 groups. According to linear regression analysis, expression levels of TR-α1, and -α2 were positively and negatively correlated with those of α-MHC, respectively. Conclusions - We conclude that decreases in TR-α1 and increases in TR-α2 may lead to local attenuation of thyroid hormone signaling in the failing human heart and that the resulting tissue-specific hypothyroidism is a candidate for the molecular mechanism that induces fetal gene expression in the failing human ventricle.

Original languageEnglish (US)
Pages (from-to)1089-1094
Number of pages6
JournalCirculation
Volume103
Issue number8
DOIs
StatePublished - Feb 27 2001

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Keywords

  • Heart failure
  • Hormones
  • Myosin
  • Receptors
  • Thyroid

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kinugawa, K., Minobe, W. A., Wood, W. M., Ridgway, E. C., Baxter, J. D., Ribeiro, R. C. J., Tawadrous, M. F., Lowes, B. A., Long, C. S., & Bristow, M. R. (2001). Signaling pathways responsible for fetal gene induction in the failing human heart: Evidence for altered thyroid hormone receptor gene expression. Circulation, 103(8), 1089-1094. https://doi.org/10.1161/01.CIR.103.8.1089