Circulation Research. 2001;89:591-598
Published online before print September 13, 2001, doi: 10.1161/hh1901.096706
Published online before print September 13, 2001, doi: 10.1161/hh1901.096706
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Regulation of Thyroid Hormone Receptor Isoforms in Physiological and Pathological Cardiac Hypertrophy
From the Division of Cardiology (K.K., M.R.B.), University of Colorado Health Sciences Center, Denver, Colo; Department of Cardiovascular Medicine (K.Y., Y.E., T.A.), Graduate School of Medicine, University of Tokyo, Japan; Department of Pharmaceutical Sciences (R.C.J.R.), University of Brasília, Brazil; Metabolic Research Unit, Diabetes Center, and Department of Medicine (J.D.B.), University of California, San Francisco, Calif; Department of Medicine (Cardiology) (S.A.C.), San Francisco General Hospital, San Francisco, Calif; Cardiology Section (C.S.L.), Denver Health Medical Center, Denver, Colo; and Veterans Affairs Medical Center and Cardiovascular Research Institute and Department of Medicine (P.C.S.), University of California, San Francisco, Calif.
Correspondence to Paul C. Simpson, MD, VA Medical Center (111-C-8), 4150 Clement St, San Francisco, CA 94121. E-mail pcs{at}itsa.ucsf.edu
Abstract — Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including 
- and ß-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) ß1, 1, and 2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, - and ß-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 TRß1 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 TRß1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRß1 to transcription of ß-MyHC, SERCA, and TRß1, and TR1 to -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.
Key Words: thyroid hormone receptor • physiological and pathological hypertrophy • 1-adrenergic receptor • cardiac myocyte • rat
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