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Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy

K Kinugawa1, K Yonekura, R C Ribeiro

  • 1Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO, USA.

Circulation Research
|September 29, 2001
PubMed

Insights

Thyroid hormone receptors (TRs) in heart cells change with cardiac hypertrophy. TR levels are altered, explaining molecular changes in both physiological and pathological heart enlargement.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Endocrinology

Background:

  • Cardiac hypertrophy involves altered gene expression of thyroid hormone (TH)-responsive genes like alpha- and beta-myosin heavy chain (MyHC) and SERCA.
  • TH treatment can reverse pathological hypertrophy, suggesting a role for TH signaling, yet serum TH levels are often normal.

Purpose of the Study:

  • To investigate the regulation and distinct functions of thyroid hormone receptor (TR) subtypes (TRbeta1, TRalpha1, TRalpha2) in rat cardiac hypertrophy models.
  • To determine if changes in myocyte TR levels contribute to the molecular phenotypes observed in physiological and pathological cardiac hypertrophy.

Main Methods:

  • Studied TR subtype expression in rat cardiac hypertrophy models induced by phenylephrine (in culture) and pressure overload (in vivo).
  • Examined TR expression in models mimicking hypothyroid-like and hyperthyroid-like states.
  • Utilized myocyte culture experiments with TR overexpression, triiodothyronine (T3) treatment, and TR isoform-selective agonists (GC-1) to assess functional coupling.

Main Results:

  • All three TR subtypes were downregulated in hypertrophy models with a hypothyroid-like mRNA phenotype (phenylephrine, pressure overload).
  • Myocyte TRbeta1 was upregulated in models with a hyperthyroid-like phenotype (T3, exercise).
  • TRbeta1 was linked to beta-MyHC, SERCA, and TRbeta1 transcription, while TRalpha1 influenced alpha-MyHC transcription and myocyte size.

Conclusions:

  • Thyroid hormone receptor isoforms (TRbeta1, TRalpha1) exhibit distinct regulation and functional roles in rat cardiac myocytes.
  • Altered expression of myocyte TRs contributes to the molecular characteristics of physiological and pathological cardiac hypertrophy.

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