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 &agr;- and &bgr;-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) &bgr;1, &agr;1, and &agr;2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, &agr;- and &bgr;-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 TR&bgr;1 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 TR&bgr;1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TR&bgr;1 to transcription of &bgr;-MyHC, SERCA, and TR&bgr;1, and TR&agr;1 to &agr;-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.

[1]  Charles M. Bishop,et al.  Tissue-specific regulation of thyroid hormone receptor mRNA isoforms and target gene proteins in domestic ducks. , 2000, The Journal of endocrinology.

[2]  M. Weiner,et al.  Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts. , 1997, The Journal of clinical investigation.

[3]  J. Scheuer,et al.  Physiologic cardiac hypertrophy corrects contractile protein abnormalities associated with pathologic hypertrophy in rats. , 1982, The Journal of clinical investigation.

[4]  W. Giles,et al.  Cardiac Ion Channel Expression and Contractile Function in Mice with Deletion of Thyroid Hormone Receptor α or β1 , 2001 .

[5]  C. Long,et al.  Interleukin-1β Is a Negative Transcriptional Regulator of α1-Adrenergic Induced Gene Expression in Cultured Cardiac Myocytes* , 1996, The Journal of Biological Chemistry.

[6]  L. Karns,et al.  Expression of a constitutively activated mutant of the beta-isozyme of protein kinase C in cardiac myocytes stimulates the promoter of the beta-myosin heavy chain isogene. , 1991, The Journal of biological chemistry.

[7]  M. Lazar.  Thyroid hormone receptors: multiple forms, multiple possibilities. , 1993, Endocrine reviews.

[8]  C. Long,et al.  Transcription of early developmental isogenes in cardiac myocyte hypertrophy. , 1989, Journal of molecular and cellular cardiology.

[9]  G. Brent,et al.  Thyroid Hormone Receptor Gene Knockouts , 1998, Trends in Endocrinology & Metabolism.

[10]  P. Macchia,et al.  Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  B. Nadal-Ginard,et al.  Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated. , 1984, The Journal of biological chemistry.

[12]  K. Yamauchi,et al.  Molecular cloning and characterization of the promoter region of the human c-erbAα gene , 1993 .

[13]  P. Simpson,et al.  Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat. , 2000, Circulation research.

[14]  E. Lakatta,et al.  Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[15]  L. Karns,et al.  An enhancer core element mediates stimulation of the rat beta-myosin heavy chain promoter by an alpha 1-adrenergic agonist and activated beta-protein kinase C in hypertrophy of cardiac myocytes. , 1994, The Journal of biological chemistry.

[16]  R. Wahl,et al.  Influence of thyroid hormones and catecholamines on myosin of swim-exercised rats. , 1990, Journal of applied physiology.

[17]  J. Scheuer,et al.  Cardiac conditioning ameliorates cardiac dysfunction associated with renal hypertension in rats. , 1984, The Journal of clinical investigation.

[18]  I. Klein,et al.  Time course of the in vivo effects of thyroid hormone on cardiac gene expression. , 1992, Endocrinology.

[19]  T. Visser,et al.  Uptake of thyroid hormones in neonatal rat cardiac myocytes. , 1996, Endocrinology.

[20]  M. Lazar,et al.  Widespread distribution of immunoreactive thyroid hormone beta 2 receptor (TR beta 2) in the nuclei of extrapituitary rat tissues. , 1994, The Journal of biological chemistry.

[21]  W. Frishman,et al.  Thyroid hormone and cardiovascular disease. , 1998, American heart journal.

[22]  J. Baxter,et al.  Thyroid Hormone Export Regulates Cellular Hormone Content and Response* , 1996, The Journal of Biological Chemistry.

[23]  M. Willingham,et al.  Intracellular distribution of the endogenous and transfected beta form of thyroid hormone nuclear receptor visualized by the use of domain-specific monoclonal antibodies. , 1991, Endocrinology.

[24]  J. Baxter,et al.  Thyroid hormone alters in vitro DNA binding of monomers and dimers of thyroid hormone receptors. , 1992, Molecular endocrinology.

[25]  G. Williams,et al.  Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms , 2000, Molecular and Cellular Biology.

[26]  W. Dillmann.  Biochemical basis of thyroid hormone action in the heart. , 1990, The American journal of medicine.

[27]  C. Long,et al.  Signaling Pathways Responsible for Fetal Gene Induction in the Failing Human Heart: Evidence for Altered Thyroid Hormone Receptor Gene Expression , 2001, Circulation.

[28]  F. Haddad,et al.  Thyroid receptor plasticity in striated muscle types: effects of altered thyroid state. , 1998, American journal of physiology. Endocrinology and metabolism.

[29]  T. Miyamoto,et al.  Cloning and characterization of the human thyroid hormone receptor beta 1 gene promoter. , 1992, Biochemical and biophysical research communications.

[30]  K. Umesono,et al.  Determinants of target gene specificity for steroid/thyroid hormone receptors , 1989, Cell.

[31]  M. Hixon,et al.  Calcineurin is activated in rat hearts with physiological left ventricular hypertrophy induced by voluntary exercise training. , 2000, Circulation.

[32]  A. Moriscot,et al.  Transcription of the rat sarcoplasmic reticulum Ca2+ adenosine triphosphatase gene is increased by 3,5,3'-triiodothyronine receptor isoform-specific interactions with the myocyte-specific enhancer factor-2a. , 1997, Endocrinology.

[33]  R. Chizzonite,et al.  Regulation of myosin isoenzyme composition in fetal and neonatal rat ventricle by endogenous thyroid hormones. , 1984, The Journal of biological chemistry.

[34]  J. Baxter,et al.  A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. , 1998, Chemistry & biology.

[35]  P. McLaughlin,et al.  Favorable left ventricular remodeling following large myocardial infarction by exercise training. Effect on ventricular morphology and gene expression. , 1995, The Journal of clinical investigation.

[36]  B. Gloss,et al.  The Thyroid Hormone Receptor-β-Selective Agonist GC-1 Differentially Affects Plasma Lipids and Cardiac Activity. , 2000, Endocrinology.

[37]  R. Matsuoka,et al.  Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. , 1987, The Journal of clinical investigation.

[38]  B. Nadal-Ginard,et al.  Myocyte-specific enhancer factor 2 and thyroid hormone receptor associate and synergistically activate the alpha-cardiac myosin heavy-chain gene , 1997, Molecular and cellular biology.

[39]  D. Forrest,et al.  Functions of thyroid hormone receptors in mice. , 2000, Thyroid : official journal of the American Thyroid Association.

[40]  C. Long,et al.  Cloning of the rat alpha 1C-adrenergic receptor from cardiac myocytes. alpha 1C, alpha 1B, and alpha 1D mRNAs are present in cardiac myocytes but not in cardiac fibroblasts. , 1994, Circulation research.

[41]  R. Fletterick,et al.  Mechanisms of thyroid hormone action: insights from X-ray crystallographic and functional studies. , 1998, Recent progress in hormone research.

[42]  Karl H. Pribram,et al.  Functions of the , 1954 .

[43]  C. Long,et al.  Interleukin-1 beta induces cardiac myocyte growth but inhibits cardiac fibroblast proliferation in culture. , 1995, The Journal of clinical investigation.

[44]  Donald F. Tapley,et al.  THE MECHANISM OF ACTION OF THYROID HORMONES , 1962 .