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

Abstract

Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca(2+)-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) beta1, alpha1, and alpha2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, alpha- and beta-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 TRbeta1 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 TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and TRalpha1 to alpha-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.

• Authors: K Kinugawa, K Yonekura, R C Ribeiro, Y Eto, T Aoyagi, J D Baxter, S A Camacho, M R Bristow, C S Long, P C Simpson
• Journal: Circulation research (Circ Res) Vol. 89 Issue 7 Pg. 591-8 (Sep 28 2001) ISSN: 1524-4571 [Electronic] United States
• PMID: 11577024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Protein Isoforms
• RNA, Messenger
• Receptors, Thyroid Hormone
• Triiodothyronine
• Phenylephrine
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Myosin Heavy Chains
• Calcium-Transporting ATPases

Topics

• Animals
• Calcium-Transporting ATPases (genetics, metabolism)
• Cardiomegaly (physiopathology)
• Cells, Cultured
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Male
• Motor Activity
• Myocardium (cytology, metabolism)
• Myosin Heavy Chains (genetics, metabolism)
• Phenotype
• Phenylephrine (pharmacology)
• Physical Conditioning, Animal
• Protein Isoforms (agonists, genetics, metabolism)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Receptors, Thyroid Hormone (agonists, genetics, metabolism)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Transfection
• Triiodothyronine (pharmacology)