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
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Abstract |
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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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Introduction |
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Cardiac hypertrophy is sometimes considered a single process that leads invariably to myocardial dysfunction (pathological hypertrophy). However, physiological hypertrophy exists in which cardiac function is maintained or enhanced, including normal cardiac development, exercise training, and thyroid hormone (TH) treatment. Exercise and TH can reverse molecular and functional abnormalities in pathological hypertrophy without decreasing ventricular mass, indicating that physiological and pathological hypertrophy are qualitatively distinct processes.1–6
TH-responsive genes in cardiac muscle include -myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA), which are induced by TH, and ß-MyHC, which is repressed.7,8 An intriguing observation is that pathological hypertrophy is characterized by hypothyroid-like changes in these target genes, with decreases in -MyHC and SERCA and increases in ß-MyHC, a molecular phenotype also called the fetal program.9 The fact that TH treatment can reverse these genetic changes in some models of pathological hypertrophy is additional evidence for a hypothyroid state, but TH blood levels are usually normal.3 Conversely, physiological hypertrophy caused by exercise is characterized by hyperthyroid-like changes in TH target genes, yet again blood TH levels are normal.10 Only in cardiac hypertrophy during normal postnatal development are changes in TH-responsive genes attributable clearly to altered TH levels.11,12
Transcription of TH target genes is mediated by nuclear TH receptors (TRs), with 2 genes, and ß, encoding at least 4 major TRs, ß1, ß2, 1, and 2,13,14 as well as minor variants, including TRß3.15 TRs ß1, 1, and 2 are expressed widely. TRß2 is present mainly in pituitary cells but might be a small fraction of T3-binding TRs in heart, as found in one study.16 TR2 binds thyroid response elements (TREs) on DNA but does not bind 3,3',5-triiodo-L-thyronine (T3), the active form of TH, and can function as a dominant negative.13,17 TRs ß1 and 1 bind T3 with similar affinity but exhibit subtle differences in binding to TREs and cofactors and in forming homodimers and heterodimers with retinoid X receptors.13,18–20 Consistent with these biochemical differences, mouse TR knockouts reveal nonredundant TR functions in many tissues.19–21 In the heart, however, TR knockouts suggest that the transcription effects of TH are mediated largely by TR1.17,22 TR functions have not been evaluated systematically in isolated myocytes.
In this study, we tested the hypothesis that hypothyroid- and hyperthyroid-like transcription changes in pathological and physiological hypertrophy are caused by altered TR levels in heart and myocytes. Recent studies in the aging rat and in human end-stage heart failure reveal changes in myocardial TR levels that correlate with changes in TH target gene transcription.23,24 However, possible changes in TR levels in hypertrophy have not been examined, and TR functions on target promoters in myocytes have not been compared. We measured TRs in rat hypertrophy models in culture and in vivo and tested TR functions in culture using transfection and treatment with T3 or a TRß1-selective agonist.
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Materials and Methods |
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Cell Culture, Hypertrophy, and Transfection
Ventricular myocytes from 1-day-old rats were plated at low density in MEM with 5% calf serum and studied in serum-free MEM exactly as in Deng et al.25 Cardiac nonmyocytes in preplates were expanded to near confluence in MEM with 5% serum.26 Cultures were treated with phenylephrine (PE) (Sigma No. P6126), T3 (Sigma No. T5516), GC-1 (gift from G. Chiellini and T.S. Scanlan, Department of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, Calif),18 or their vehicles (ascorbic acid for PE, NaOH for T3, and DMSO for GC-1). Myocyte hypertrophy was quantified by content of radiolabeled protein (RLP) after continuous incubation with 14C- or 3H-phenylalanine. Myocytes were doubly transfected using calcium phosphate coprecipitation27 with expression plasmids for the human TRs under control of the cytomegalovirus promoter (CMV)28 and chloramphenicol acetyl transferase (CAT) reporter plasmids containing the rat promoters for
-MyHC (2900 bp), ß-MyHC (3300 bp), or SERCA (3500 bp).29
Hypertrophy In Vivo
Hypertrophy was induced in adult male Wistar rats by voluntary wheel running for 10 weeks (age 7 to 17 weeks) or by ascending aortic constriction (pressure gradient 
75 mm Hg) for 4 weeks (age 10 to 14 weeks).30 Serum levels of total 3,3',5,5'-tetraiodo-L-thyronine (T4) and total T3 were measured by ELISA (ICN Pharmaceuticals).
RNase Protection Assay (RPA) for TH-Responsive mRNAs
Total RNA was extracted from cells or ventricles with TRIZol (GIBCO) and used in RPA with a probe for - and ß-MyHC and a probe for SERCA2a plus GAPDH as an internal control (see expanded Materials and Methods, available in the online data supplement at http://www.circresaha.org).25
TH Receptors
For TR mRNAs, RPA was used with probes specific for the rat TR isoforms, and GAPDH was used as an internal control (see the expanded Materials and Methods section).24 For TR proteins, cultured myocyte nuclear and cytoplasmic fractions27 were used in Western blot with monoclonal antibodies from Santa Cruz (J51/SC-737 specific for human TRß1; J52/SC-738 reactive with rat and human TRß1).31 Human and rat TRß1 proteins for standards were synthesized using rabbit reticulocyte lysate (TNT T7 Quick Coupled Transcription/Translation System, Promega).28,32
Statistics
Data shown are mean±SE and were compared by one-way ANOVA and the Newman-Keuls test.
An expanded Materials and Methods section can be found in the online data supplement available at http://www.circresaha.org.
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Results |
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TH-Responsive mRNAs in Hypertrophy Models in Culture and In Vivo
We first confirmed regulation of TH target mRNAs in cardiac hypertrophy models in culture and in vivo (Table 1). In cultured neonatal rat myocytes, TH (T3 100 nmol/L) caused hypertrophy, increased
-MyHC and SERCA mRNA levels, and repressed ß-MyHC to 5% of control. The 1-adrenergic receptor (AR) hypertrophic agonist PE (20 µmol/L) had opposite effects on these mRNAs, increasing ß-MyHC and decreasing SERCA and -MyHC. Prazosin (2 µmol/L) inhibited all PE effects, confirming 1-AR dependence (n=3 cultures, data not shown).
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Under our basal, serum-free culture conditions, medium T3 levels averaged about 0.1 nmol/L over the 3-day time course of these experiments, presumably reflecting myocyte release of stored T3.33–35 Interestingly, when 1000-fold excess T3 (100 nmol/L) was added to PE-treated myocytes, all PE effects on TH-responsive transcripts were reversed, with significant increases in -MyHC and SERCA and decreases in ß-MyHC (Table 1). The antagonistic relationship between 1-AR and T3 signaling was not explained by a lesser degree of hypertrophy, because hypertrophy was even greater with PE plus T3 (Table 1).
In intact rat hypertrophy models, voluntary running exercise stimulated hypertrophy with an mRNA profile similar to T3 in culture (Table 1). Conversely, pressure overload by ascending aortic constriction caused hypertrophy with changes in TH target mRNAs opposite to exercise and similar to PE in culture (Table 1). Thus, in agreement with previous studies (discussed in the Introduction), 2 hypertrophy models had signature mRNA changes of heightened thyroid signaling, T3 in culture and exercise in vivo. In contrast, 2 other models had a directionally opposite pattern of hypothyroid-like signaling, PE in culture and pressure overload in vivo. T3 and T4 blood levels in the intact rat models were similar among all 4 groups, with total T4 40 nmol/L (3 to 3.2 µg/dL) and total T3 1 nmol/L (52 to 55 ng/dL) (n=6 to 13, P=NS), as found by others.3,10 Thus, mRNA changes were not explained by changes in circulating TH concentration.
TR Levels in Hypertrophy Models in Culture
To test if some change in thyroid signaling besides TH concentration might explain changes in transcription of TH-responsive genes in hypertrophy, we first measured TR levels in cultured myocytes. In cultured myocytes under basal, serum-free conditions, RPAs detected the mRNAs for TRs 2, 1, and ß1, with a molar ratio of 7:3:1. TRß2 mRNA was not found, using a probe validated in rat pituitary GC cells (not shown), and TRß3 was not tested. Treatment with T3 under conditions that stimulated hypertrophy (Table 1) caused an increase in TRß1 mRNA, with a maximum 2-fold and an EC50 3 nmol/L, but had no effect on TR2 or 1 (Figure 1A). T3 induction of TRß1 in myocytes was significant as early as 12 hours and maximum at 48 hours (data not shown). Thus TRß1 itself was a TH-responsive gene in myocytes and was increased in T3-stimulated hypertrophy.
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PE-induced hypertrophy in cultured myocytes had an effect different from T3 and reduced the levels of all 3 TR isoform mRNAs to 50% to 75% of control (Figure 1B). The EC50 for TR repression was about 3 µmol/L (Figure 1B), similar to the EC50 for PE-induced hypertrophy, and the PE effect was detected as early as 6 hours (data not shown). PE is an 1-AR agonist with weak ß-AR activity, and specific 1-AR repression of TRs was confirmed in separate experiments with norepinephrine, isoproterenol, prazosin, and timolol (all 2 µmol/L, n=3 to 4 cultures for each, data not shown). Interestingly, and similar to the other TH target mRNAs (Table 1), addition of T3 reversed PE repression of TRß1, but TRs 1 and 2 were not changed (Figure 1B).
To test if TR mRNA levels reflected TR protein, we measured endogenous TRs in cultured myocytes by Western blot. None of the commercial antibodies from Santa Cruz or Affinity BioReagent gave specific signals for TRs 1 and 2 (not shown), but TRß1 protein was detected in nuclear extracts (Figure 1). PE reduced TRß1 protein significantly, whereas T3 increased TRß1 and reversed TRß1 repression caused by PE (Figures 1A and 1B). Thus TRß1 mRNA and protein changes were concordant.
Cultured cardiac nonmyocytes also expressed mRNAs for all 3 of the TRs found in myocytes, 1, 2, and ß1, but levels were not altered by PE 20 µmol/L or T3 100 nmol/L (n=3 cultures, data not shown). No response to PE can be explained by the absence of 1-ARs in nonmyocytes.36 No response to T3 is compatible with a requirement for cell-specific factors such as MEF-2 in myocyte TR signaling.37,38
TR mRNA Levels in Hypertrophy Models In Vivo
Control adult male rat hearts contained mRNAs for TRs 2, 1, and ß1 at equal molar ratios (1:1:1). Physiological hypertrophy stimulated by voluntary running exercise mimicked T3 in culture, with an increase in TRß1 mRNA and no change in TRs 1 and 2 (Figure 2). Pathological hypertrophy stimulated by ascending aortic constriction was similar to PE in culture, with decreases in all 3 TR isoform mRNAs (Figure 2), detectable as early as 1 week after banding (not shown). Thus, in distinct hypertrophy models in vivo as in culture, TR isoform levels and TH-responsive transcript levels were related directly (Figure 2 and Table 1).
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Cotransfection of TR Isoforms and TH-Responsive Promoters
To test directly whether changes in TR levels could alter TH-responsive transcription, we cotransfected cultured myocytes with expression plasmids for the human TR isoforms and reporter plasmids for the TH-responsive genes (Figure 3). The Western blot in Figure 3A shows that human TRß1 was detected in nuclear extracts from TRß1-transfected myocytes, with overflow of transfected TRß1 into the cytosolic fraction, suggesting saturating levels.31 Similarly, an antibody recognizing both human and rat TRß1 indicated that total TRß1 nuclear levels in transfected cultures were about 2-fold over endogenous (Figure 3A). With 5% of myocytes transfected,39 this result implied about 40-fold overexpression of TRß1.
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We used this system to test the effects of increasing TR isoform levels on -MyHC, ß-MyHC, and SERCA promoters. In vehicle-treated control myocytes, overexpression of TR1 activated the -MyHC promoter, and TRß1 repressed ß-MyHC (Figure 3B). TR2 had no effect. Induction of -MyHC indicated that TR1 was expressed, even though Western blots were unsatisfactory for TR protein levels.
In PE-treated myocytes transfected with empty vector, the ß-MyHC promoter was activated, and -MyHC and SERCA promoters were repressed (Figure 3C), similar to the PE effects on endogenous mRNAs (Table 1). Increasing the levels of TR1 by transfection reversed PE repression of -MyHC, whereas TRß1 overexpression significantly opposed the effects of PE on both ß-MyHC and SERCA. Interestingly, forced expression of TR2, the non-T3-binding TR, slightly but significantly enhanced PE repression of -MyHC and SERCA (Figure 3C).
In T3-treated myocytes transfected with empty vector, the ß-MyHC promoter was repressed and -MyHC and SERCA were activated (Figure 3D), as expected from T3-induced mRNA changes (Table 1). Overexpression of TRß1 in T3-treated myocytes significantly enhanced induction of the SERCA promoter, but TRs 1 and 2 had no effects over T3 alone (Figure 3D).
Taken together, these cotransfection results showed that increasing the levels of T3-binding TRs altered TH-responsive transcription and antagonized the effects of PE on TH-responsive genes. In addition, the results suggested different functions of TRs in myocytes, regulation of -MyHC by TR1, and regulation of ß-MyHC and SERCA by TRß1. The repressive effect of TR2 only in PE-treated cells (Figure 3C) was consistent with a weak dominant-negative effect of this non–T3-binding TR (see the Introduction) that could be detected only when levels of the T3-binding TRs were reduced by PE (Figure 1B).
Effects of a TRß1-Selective Agonist on Myocyte Transcription and Hypertrophy
To test different functional roles for TR isoforms by a second approach not involving transfection, we treated myocytes with GC-1, which has 10-fold selectivity for TRß1 versus TR1 but has not been tested with TRs ß2 and ß3, and compared the responses to T3, which binds with similar affinity to both TRs ß1 and 1.18,35 We assayed both TH-responsive promoter activities and endogenous mRNAs (Figures 4A and 4B) and also RLP, an index of total protein content or overall myocyte size (Figure 4C). As shown in Figures 4A through 4C and summarized in Table 2, the EC50s for GC-1 induction of SERCA and repression of ß-MyHC were identical to the EC50s for T3, whereas GC-1 was at least 10-fold less potent than T3 in induction of -MyHC and RLP. These data were consistent with the cotransfection experiments (Figure 3) and suggested preferential coupling of TRß1 to ß-MyHC and SERCA, whereas TR1 regulated -MyHC and total protein content. In addition, GC-1 increased TRß1 mRNA by 203±28% at 100 nmol/L with an EC50 of 2 nmol/L (P<0.05 versus vehicle, n=5), almost identical to the effect of T3 (Figure 1 and Table 2), consistent with the notion that TRß1 activated its own transcription.
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Discussion |
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The main new finding in this study was the direct relationship between TR levels and transcription of TH-responsive genes in different types of hypertrophy. All TRs were downregulated in pressure overload, a model of pathological hypertrophy with a hypothyroid-like molecular phenotype. Conversely, TRß1 was upregulated in the exercise model of physiological hypertrophy, where TH-responsive transcription was enhanced. These results, together with the TR overexpression experiments in cultured myocytes, suggest that the distinct molecular signatures in different types of hypertrophy can be caused in part by altered TR levels. Thus the fetal program in pathological hypertrophy can be viewed as the result of cellular hypothyroidism, caused by reduced TR levels, whereas physiological hypertrophy can be seen as a state of relative cellular hyperthyroidism, attributable to increased TRß1. The results also indicate that TR isoforms have different transcription functions in rat myocytes and raise the possibility of additional alteration of TH signaling in hypertrophy.
We detected 3 TRs in rat myocytes, ß1, 1, and 2, and all were reduced by pressure overload in vivo and 1-AR signaling in culture (Figures 1 and 2), the models with hypothyroid-like transcription changes (Table 1). Reversal of hypothyroid signaling when TRs ß1 and 1 were overexpressed in the PE culture model supported the causal significance of TR downregulation (Figure 3C). Downregulation of dominant-negative TR2 in both models would have been expected to partly counteract the hypothyroid effects of decreased TRs ß1 and 1, because overexpressed TR2 had hypothyroid effects when TRs ß1 and 1 were reduced by PE (Figure 3C). Nevertheless, global TR downregulation in both models of pathological hypertrophy was associated with reduced transcription of TH target genes.
Abnormal TR levels are also seen at a terminal stage of pathological hypertrophy, severe human heart failure. In human heart failure, TR1 is decreased and TR2 is increased, probably because of altered splicing of the TR gene, and the increase in TR2 correlates with reduced -MyHC transcription.24 In our rat models of PE treatment and pressure overload, the global decrease in all TR mRNAs could be explained by reduced TR gene transcription or increased TR mRNA degradation. Thus the specific mechanism for altered TR levels might differ among species or models, but the human and rat studies both suggest that TR downregulation is a mechanism for hypothyroid-like signaling in pathological hypertrophy. This relationship was additionally strengthened by our converse results in physiological models.
TR upregulation was seen in exercise, a model of physiological hypertrophy with normal or enhanced contractile function.30 Voluntary running exercise caused an increase in TRß1 but no change in TR (Figure 2). T3 in culture also caused selective induction of TRß1 (Figure 1) and similarly induces a physiological hypertrophy in vivo.5 Our finding that the TRß1 gene is TH-responsive in myocytes but the TR gene is not agrees with some studies in the intact rat,40,41 but not with others,42 and can be explained by positive TREs in the TRß1 promoter that are absent in TR.43,44 Furthermore, the TRß1 gene seemed to be activated by TRß1 itself, because T3 and the TRß1-selective agonist GC-1 induced TRß1 with similar potency (Table 2). Thus, exercise-induced increases in TRß1 levels should be partly self-sustaining, and the increase in TRß1 would augment transcription of downstream TH target genes on the basis of our transfection studies (Figure 3).
TRß1 in myocytes differed from TR1 in induction by T3 and also in function. In this study, we made the first systematic comparison of TR function in isolated myocytes and found by 2 complimentary approaches that TRß1 induced SERCA and TRß1 itself and repressed ß-MyHC, whereas TR1 increased -MyHC and protein content (Figures 3 and 4 and Table 2). Notably, the same pattern of TR function was seen with TR cotransfection and with GC-1, which has 10-fold selectivity for TRß1.18 Distinct TR isoform effects on different promoters might be explained by isoform-specific interactions with cofactors or differing affinities for TREs (see the Introduction). Interestingly, target gene–specific differences were evident even for a single TR isoform in that TRß1 more potently repressed ß-MyHC than it activated SERCA and activated SERCA more potently than TRß1 itself (Table 2). Also intriguing was the correlation of TR1 signaling with increased total protein content, an index of overall hypertrophy (Figure 4C and Table 2). Increased protein content requires increased translation as well as transcription, thus raising the question of nongenomic effects of T3 via TR1.
Previous results from rat and human models are consistent with the distinct transcription functions of TR isoforms we show in this study. In the aging rat, increased ß-MyHC transcription correlates with decreased TRß1 levels and reduced -MyHC correlates with reduced TR1.23 A correlation between levels of TR1 and -MyHC is also seen in the failing human heart.24 A preferential effect of GC-1 on myocardial SERCA and ß-MyHC is not seen in the rat in vivo, but this might be because of lower bioavailability of GC-1 in cardiac tissue.35 On the other hand, the mouse might be different from rat and human, because knockout studies suggest that most cardiac effects of T3 can be accounted for by TR1.17,22 Whether both TRs are required for full TH effects in heart is one key consideration in potential therapeutic uses of TH signaling,8 and additional study is needed.
Finally, the question arises of whether other mechanisms alter TH signaling in hypertrophy in addition to changes in TR levels. Pertinent is the effect of T3 in the culture model, where a 1000-fold increase in medium T3 (from 0.1 to 100 nmol/L) reversed PE antagonism of all TH-responsive genes, including the MyHCs, SERCA, and TRß1, despite PE reduction of TR levels (Table 1 and Figure 1). Thus, excess T3 in culture could counteract the hypothyroid effects of reduced TRs. In vivo as well, high doses of T3 reverse hypothyroid transcription in pressure overload models3,5 despite the reduced TR levels we show in this study (Figure 2). The reversal effect of excess T3 can be explained partly by induction of TRß1 and downstream changes in other TH-responsive genes, but the T3 effect also suggests that cellular T3 levels might be limiting in some cases. Thus it is possible that myocyte T3 metabolism33–35 is changed in hypertrophy, with increases in cellular T3 with exercise and decreases with pressure overload and PE, and this requires additional study.
In summary, changes in TR levels can explain at least in part the characteristic hypothyroid- and hyperthyroid-like transcription in different types of hypertrophy. TH signaling is impaired in pathological hypertrophy and enhanced in physiological hypertrophy.
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Acknowledgments |
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This work was supported in part by grants from the National Institutes of Health to P.C.S. and C.S.L. J.D.B. is consultant and Deputy Director for Karo Bio AB, which has commercial interests in this area of research. We thank Marietta Paninbatan, Heather Lucas, Anna Casulo, Yuren Wei, Gail Morris, and Mary Atz for excellent technical assistance.
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Footnotes |
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Presented in part at the 71st and 73rd Scientific Sessions of the American Heart Association, Dallas, Tex, November 8–11, 1998, and New Orleans, La, November 12–15, 2000, and published in abstract form (Circulation. 1998;98[suppl I]:I-837 and 2000;102[suppl II]:II-72).
Received June 19, 2001; accepted July 27, 2001.
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