TY - JOUR
T1 - Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy
AU - Kinugawa, Koichiro
AU - Yonekura, Katsunori
AU - Ribeiro, Ralff C.J.
AU - Eto, Yoko
AU - Aoyagi, Teruhiko
AU - Baxter, John D.
AU - Camacho, S. Albert
AU - Bristow, Michael R.
AU - Long, Carlin S.
AU - Simpson, Paul C.
PY - 2001/9/28
Y1 - 2001/9/28
N2 - Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including α- and β-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) β1, α1, and α2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, α- and β-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRβ1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRβ1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRβ1 to transcription of β-MyHC, SERCA, and TRβ1, and TRα1 to α-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.
AB - Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including α- and β-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) β1, α1, and α2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, α- and β-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRβ1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRβ1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRβ1 to transcription of β-MyHC, SERCA, and TRβ1, and TRα1 to α-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.
KW - Cardiac myocyte
KW - Physiological and pathological hypertrophy
KW - Rat
KW - Thyroid hormone receptor
KW - α-adrenergic receptor
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U2 - 10.1161/hh1901.096706
DO - 10.1161/hh1901.096706
M3 - Article
C2 - 11577024
AN - SCOPUS:0035964923
SN - 0009-7330
VL - 89
SP - 591
EP - 598
JO - Circulation research
JF - Circulation research
IS - 7
ER -