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Cardiac Expression and Function of Thyroid Hormone Receptor ß and Its PV Mutant

Division of Endocrinology and Metabolism (E.A.S., B.G., D.D.B., W.H.D.), University of California San Diego, La Jolla, California 92093 and Laboratory of Molecular Biology (M.K., S.C.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Wolfgang H. Dillmann, Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0618. E-mail: wdillman{at}ucsd.edu.

	Abstract

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Thyroid hormone (T₃) influences cardiac function, and mice with deletion of thyroid hormone receptor (TR) have diminished cardiac function. TR1 represents 70% and TRß1 represents the remaining 30% of TR in ventricular myocytes, and its role in cardiac function is not well established. To determine the role of TRß1 in detail, we compared contractility in isolated perfused hearts from wild-type (WT) and TRß knockout mice under normal and increased work load. TRß knockout hearts showed contractile function similar to WT hearts at baseline and under conditions of enhanced demand. To gain insight into the role of TRß, we used mice with a homozygous mutation in exon 10 of TRß encoding the dominant negative PV mutant (TRßPV) expressed from the endogenous TRß promoter. TRßPV mice treated with 6-propyl-2-thiouracil and supplemented with T₃ to make them euthyroid have decreased contractility with negative and positive rates of relaxation and contraction as well as peak systolic pressure diminished by 35 ± 5, 34 ± 6, and 35 ± 6% in comparison with WT mice. Heart rate is diminished by 36 ± 7%, which is accompanied by decreased expression of the pacemaker-related gene hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4). The expression of TRß1 in the pacemaker myocytes of the sinoatrial node was confirmed by quantitation of TR1 and TRß1 mRNA in sinoatrial node, which showed that TRß1 mRNA represents 27.5 ± 1.6% of the ligand-binding isoforms of the TR. In summary, although TRß is expressed at much lower levels in all regions of the heart than TR1, expression of the strong dominant negative TRßPV mutant results in decreased contractile function and heart rate.

	Introduction

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THYROID HORMONE (T₃) significantly influences cardiac contractile and electrophysiological function with increasing amounts of T₃ enhancing cardiac contractile function and accelerating heart rate (1, 2). These effects are mediated through the actions of two genes coding for the T₃ ligand receptors, thyroid hormone receptor (TR1) and thyroid hormone receptor ß (TRß) (3). These two genes encode four ligand-binding isoforms of TR (TR1, TRß1, TRß2, and TRß3). In the ventricle of the heart, the ratio of TR1 to TRß mRNA has been found to be 3:1 (4). This indicates that both genes are expressed in the heart but that TR1 is the predominant ligand-binding isoform.

The roles of TR and TRß on cardiac function have been investigated by the use of TR knockout (KO) mice. The TRKO mice have normal T₃ levels but have a hypothyroid-like cardiac phenotype, resulting in decreased heart rate and decreased contractility (4, 5). In contrast, TRßKO mice made euthyroid exhibit normal heart rate as well as normal contractile function of papillary muscle (4). The role of TRß in the heart is, however, not completely clear. It has, for example, been reported that T₃ administration to TR1KO mice results in an increase in heart rate from a much lower baseline heart rate (6) and that for T₃-mediated increases in heart weight TRß plays an important role (7). These findings have led to the hypothesis that the TR is the dominant isoform in the heart, but TRß also contributes to T₃ cardiac action, however, with a less well-defined role. To further define the role of TRß in heart rate determination, we quantified and compared its expression with TR in the sinoatrial node (SAN), which serves as the pacemaker for heart rate generation. In relation to contractility, systolic and diastolic functions of hearts from TRßKO mice submitted to an increased contractile challenge were determined.

An alternate approach to obtain insight into TRß function is to determine the effects of a dominant negative TRß mutant generated by a knock-in approach of the mutated TRß exon 10 resulting in regional expression similar to that of wild-type (WT) TRß. We used the TRßPV mutant, which results in a severe type of resistance to thyroid hormone in humans (8). The TRßPV mutation results from a frame shift in the ligand-binding domain of the receptor, leading to a dominant negative mutant that does not bind T₃ (9). Because these mice express the mutant TRß receptor under the control of the natural promoter of the gene, it is expressed in the heart at the same level as the WT receptor. In this study, we examine mice homozygous for the TRßPV mutant gene. These animals have increased thyroid hormone levels due to the expression of the mutant in the pituitary. Additional experiments were conducted on mice that were made euthyroid through inhibition of endogenous T₃ production followed by supplementation of T₃ by daily injections. These mice had a decreased heart rate implying that TRß is expressed in the SAN and may either directly affect T₃ target genes or interfere with TR action.

	Materials and Methods

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Animal preparations
TRßKO and WT animals were generated in the laboratory of Jacques Samarut by deletion of exons 4 and 5 of the TRß gene (10). The TRßPV mutant mice and their WT littermates were generated and bred as described by Kaneshige et al. (9). All procedures were performed in accordance with the guidelines established by the University of California, San Diego Animal Subjects Program.

Normalizing T₃ levels in mice
Mice were fed for 5 wk with iodine-deficient, 0.15% 6-propyl-2-thiouracil (PTU) food pellets (Harlan-Teklad, Madison, WI). The first week, the animals were fed PTU diet to decrease their endogenous hyperthyroidism. During the remaining 4 wk, daily ip injections of T₃ (Sigma-Aldrich, St. Louis, MO) were given in saline at a dosage of 3.5 ng/g body weight. After 4 wk of this treatment, animals were used for experiments. Experiments were performed on the mice approximately 3 h after their T₃ administration for that day.

Heart rate determinations
Animals were anesthetized with separate ip injections of sodium pentobarbital (40 mg/kg) and Ketamine (40 mg/kg). Three sc limb leads were inserted into the right front leg, left front leg, and left hind leg of the mouse. After 6 min of sedation, tracings of the electrocardiogram were recorded on a personal computer with Windaq software (Data Instruments, Akron, OH). Heart rates were calculated by counting beats from 15 sec of electrocardiogram recording and were expressed in beats per minute (bpm) ± SD. Data were analyzed with a one-way ANOVA method (Systat, version 5.03, Evanston, IL). Fisher’s least significant difference post hoc tests were performed to determine the significant differences among means. P < 0.05 was considered significant.

Isolated perfused hearts
Hearts were isolated and transferred to a miniaturized Langendorff set-up for contractile studies in mouse hearts as previously described (11). In brief, hearts were removed from anesthetized mice and immersed in cold cardioplegic solution. After cannulation of the aorta, the hearts were perfused retrograde at 37 C with a modified Krebs-Henseleit buffer (in mmol/liter: 118 NaC1, 4.7 KC1, 2.25 CaC1₂, 1.2 MgSO₄, 1.2 KH₂PO₄, 25.0 NaHCO₃, 0.5 Na₂-EDTA, 5.5 glucose). A small fluid-filled balloon was inserted into the left ventricular cavity and coupled to a 2F pressure transducer (Millar Instruments, Houston, TX). The balloon was inflated until the diastolic pressure reached 10 mm Hg. Platinum wires were placed on the surface of the right atrium and used to pace the heart at 400 bpm for WT and TRßPV hearts. WT and TRßKO hearts were also paced in separate experiments at 7 Hz (420 bpm) and to increase the workload, at 10 Hz (600 bpm). Data are expressed ±SEM. Statistical comparisons were made using unpaired Student’s t tests on Microsoft Excel.

RNA extraction and ribonuclease (RNase) protection analysis
Hearts from control animals and experimentally altered mice were dissected after deep anesthesia, and the ventricle, atrium, and sinus node were dissected before the heart was frozen in liquid nitrogen. Preparation of tissue containing the sinus node of the mouse was done as described by Mangoni and Nargeot (12). The tissue was frozen at -80 C until extraction of RNA. At the same time, a small amount, equivalent to the amount of tissue of the sinus node, of the left ventricle was taken and treated the same way. Total RNA from these tissues was prepared using the RNAeasy Kit from QIAGEN (Chatsworth, CA). Contaminating DNA was removed by deoxyribonuclease I digestion of the RNA preparation when still bound to the column. Typically, a yield of 6 µg per five sinus node preparations of total RNA was achieved, of which 2 µg were used in an RNase protection experiment as previously described (4), using probes for the mouse TRß and TR1 and TR2. Isolation of tissue RNA for Northern blot was performed as described by Chomczynski and Sacchi (13). For Northern blot analysis, 15 µg of total RNA from each sample was used. Hybridization was performed using random primed cDNA probes for rat sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA)2, mouse phospholamban, and mouse hyperpolarization-activated cyclic nucleotide-gated (HCN)2 and HCN4. Oligonucleotide probes to myosin heavy chain and ß (MHC and MHCß), and 28S ribosomal RNA were labeled with [³²P]dCTP using terminal deoxynucleotide transferase and were hybridized as previously described (14). Hybridization conditions for RNase protection, generation of radiolabeled antisense RNA transcripts and processing of the RNA/RNA hybrids were previously described by our group (4). Both pacemaker ion channel probes and a control transcript (calsequestrin) were analyzed in one hybridization reaction. The protected fragments were separated on 6% acrylamide sequencing gels. Densitometry of the autoradiographs yielded digital values for each band, which were normalized to the calsequestrin signal. Data from at least three independent experiments were statistically evaluated to give the percent increases or decreases of the message levels for the pacemaker ion channels. Data are expressed ±SD. Statistical comparisons were made using unpaired Student’s t tests on Microsoft Excel.

	Results

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Physiological studies
In the TRßPV mouse, expression of the dominant negative PV mutant of the TRß is directed by the endogenous mouse TRß promoter. It has not been demonstrated whether the TRß receptor is expressed in cardiac pacemaker cells of the SAN. Expression of the dominant negative TRßPV mutant in the SAN may interfere with normal pacemaker function and result in altered heart rate in TRßPV mice. We therefore determined heart rates in WT and homozygous TRßPV mice. The average heart rate in WT mice was 568 ± 136 bpm, whereas in TRßPV mice (Fig. 1), the heart rate was significantly lower with 489 ± 62 bpm (P < 0.05). The homozygous TRßPV mice have elevated thyroid hormone levels but their heart rate is lower than that of WT mice, which is unexpected because of the elevated T₃ level. To achieve normal T₃ levels in TRßPV mice and in WT mice, both groups of animals were submitted to the same protocol, which involved making them hypothyroid by an iodine-deficient diet containing PTU and subsequent injection of a replacement dose of T₃ (3.5 ng/g of body weight). This T₃ dose induces a euthyroid status when administered to hypothyroid WT animals. WT mice submitted to this protocol had a normal heart rate of 555 ± 35 bpm. In contrast, TRßPV mice with a euthyroid status showed an even lower heart rate of 356 ± 46 bpm (P < 0.05). These results are most likely explained by the expression of the TRßPV mutant in the SAN where it may exert a dominant negative effect on the TR receptor. To determine whether this presents a likely explanation for our results, we determined whether the TRß receptor isoform is expressed in the SAN, as described below.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Heart rate in WT (568 ± 136 bpm, n = 8) and TRßPV (489 ± 62 bpm, n = 7) mice with endogenous hyperthyroidism, before and after normalization of T3 to euthyroid levels. TRßPV mice have bradycardia, which becomes more severe when T3 levels are normal [WT (eu), 555 ± 35 bpm (n = 8); TRßPV (eu), 356 ± 46 bpm (n = 7)]. *, Significant relative to WT at P < 0.05.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Contractile measurements at 420 bpm (7 Hz) and 600 bpm (10 Hz) in WT and TRßKO mice after both groups underwent normalization of T3 to euthyroid levels (eu). TRßKO had slightly but insignificantly higher contractile parameters at both stimulation frequencies. WT, n = 8; TRßKO, n = 9.

View larger version (14K): [in this window] [in a new window]   FIG. 3. Contractile measurements at a heart rate of 400 bpm in WT, TRßPV, WT (eu), and TRßPV (eu) mice. TRßPV mice have normal contractile parameters. When T3 levels are normalized, TRßPV (eu) mice have slower rates of relaxation, contraction, and peak systolic pressure (PSP) compared with WT (eu) mice. WT, n = 6; TRßKO, n = 6; WT (eu), n = 14; TRßPV (eu), n = 7. *, Significant relative to WT at P < 0.05.

View larger version (23K): [in this window] [in a new window]   FIG. 4. RNase protection with RNA from WT, TRßPV, and TRßPV (eu) mice. The levels of TR1 and TR2 mRNA are not altered by the hyperthyroidism of the TRßPV mice or by the mutant receptor. To control for equal RNA input and loading, a probe for mouse calsequestrin (CalSeq) was included.

View larger version (80K): [in this window] [in a new window]   FIG. 5. Northern blot of RNA from WT and TRßPV mice with endogenous hyperthyroidism. TRßPV mice have decreased MHCß (64%) and increased MHC (66%) and HCN2 (158%) levels.

View larger version (66K): [in this window] [in a new window]   FIG. 6. Northern blot of RNA from WT and TRßPV mice that were made euthyroid. TRßPV (eu) mice have increased MHCß (156%) and phospholamban (21%) and decreased MHC (39%) and SERCA2a (21%) levels when compared with WT (eu) mice.

View larger version (74K): [in this window] [in a new window]   FIG. 7. RNase protection with RNA from WT and TRßPV mice that were made euthyroid. TRßPV (eu) mice have decreased HCN4 levels [40% compared with WT (eu)] in the ventricle and atria, but HCN2 levels are unchanged. To control for equal RNA input and loading, a probe for mouse calsequestrin (CalSeq) was included.

View larger version (46K): [in this window] [in a new window]   FIG. 8. RNase protection with total RNA from mouse sinus node (SN) and ventricle (V). The protected bands are indicated with an arrow and designated TRß for the mouse TRß isoforms 1 and 2 or TR1 and TR2 for the mouse TR isoforms 1 and 2, respectively. To control for equal RNA input and loading, a probe for mouse calsequestrin (CalSeq) was included.

	Discussion

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The minimal role played by TRß in heart rate generation in euthyroid mice extends to TRß effects on contractile function. Hearts with deletion of TRß have normal contractile function under baseline conditions and are able to mount an appropriate response to a contractile challenge induced by pacing at an increased rate. One potential explanation for the lack of functional consequences of TRß deletion could be that TRß expression occurs only in a distinct location in the heart and therefore no general effect on contractile function occurs. To evaluate this possibility, we used mice in which exon 10 of TRß encoding the ligand-binding region was replaced by the exon 10 of the PV mutant, in which a frame-shift mutation abolishes T₃ binding and exerts a strong dominant negative effect (9). Expression of the TRßPV mutant is driven by the natural TRß promoter and occurs therefore in the same location as WT TRß. The TRßPV mutant receptor does not affect the mRNA expression of the endogenous TR. In the euthyroid TRßPV mutant mice, a decreased heart rate occurs in comparison with WT mice. The results corroborate our finding that the TRß gene is expressed in the SAN of mice.

The expression of the dominant negative TRßPV mutant leads to a relative decrease in heart rate, even in the presence of high thyroid hormone levels. This effect is most likely due to the antagonistic effect of the TRßPV on the WT TR. The effects of the mutant receptor on heart rate can be explained in part by its influence on the ion channel mRNAs HCN2 and HCN4. These genes have been identified as components of an ion channel that constitutes the I_f current, which contributes to heart rate generation (15). The HCN4 mRNA levels in the euthyroid TRßPV mice are markedly down-regulated, which could contribute to the observed decrease heart rate. It is surprising that the T₃-regulated HCN2 gene is not affected in the euthyroid TRßPV mice, which could possibly point to TRß-specific effects on the HCN4 gene.

TRßPV mutant expression leads to decreased contractile function in the heart. The rates of relaxation and contraction and the peak systolic pressure are diminished in the euthyroid TRßPV mice compared with the wild types. These effects are due to the expression of the PV mutant receptor in the myocytes of the ventricles of the heart. Although the TR receptor can compensate for the lack of the TRß gene in the TRßKO mice, the strong dominant negative effect of the mutant can diminish that compensation in these mice. The euthyroid TRßPV mice have diminished levels of SERCA2a mRNA and increased phospholamban levels, leading to diminished calcium cycling in the myocytes and decreased contractility. There is also an induction of the myosin heavy chain ß-isoform mRNA in the euthyroid TRßPV mice, which is the myosin isoform with slower contractility function and which is associated with status of diminished contractile function as it occurs in hypothyroidism, diabetes, and cardiac hypertrophy (16, 17). This could also contribute to the contractile dysfunction observed in the TRßPV mice.

Our results from TRßKO and TRßPV mutant mice indicate that deletion of TRß does not have significant electrophysiological or contractile effects. A loss of 25–30% of total TR can therefore be tolerated without significant functional impairment. Prior work has shown that T₃-responsive parameters can follow a hyperbolic or sigmoidal type of response pattern (18). With a sigmoidal response pattern, a 25–30-% loss of T₃ receptors would not translate into a significantly diminished response parameter. The relationship between TR occupancy by T₃ and the response parameter like heart rate or contractility may follow such sigmoidal response patterns. In contrast, when TRß is replaced by a dominant negative mutant of TR like the TRßPV mutant, significant impairment of electrophysiological and contractile function results. These findings imply that TRß is expressed in a ubiquitous and not a highly regional fashion in the heart. In addition, our findings indicate that a strong dominant negative TR mutant like the PV mutant can significantly interfere with the function of the more predominant TR receptor in the heart. Functional impairment indicated by a decreased heart rate and diminished contractile function only becomes apparent when TRßPV mutant mice have their elevated thyroid hormone levels lowered into the normal range. The absence of functional consequences in TRßPV mutant mice with elevated thyroid hormone levels results most likely from increased occupancy of TR1. These findings support the data shown by Zhang et al. (19) where they found no dominant negative cardiac phenotype in the TRßPV mice that were not made euthyroid. It is interesting to note that in some human beings with resistance to thyroid hormone, tachycardia is a very marked symptom in contrast to a diminished heart rate in the mouse models (20, 21). One explanation for this discrepancy may be that in the human heart, TR predominance is even higher (22) in the SAN of those patients with tachycardia and the TRß mutant mediating resistance to thyroid hormone may not be expressed at all. Increased occupancy by T₃ of TR1, with its action unopposed, would result in increased expression of T₃-responsive pacemaker ion channels thereby resulting in tachycardia.

	Acknowledgments

 
We are grateful to Dr. Bina Santoro for the plasmid containing a portion of the mouse HCN4 cDNA.

	Footnotes

 
This work was supported by grants from the National Institutes of Health (HL 25022–19) (to W.H.D.) M.K. is supported in part by the Japan Society for the Promotion of Science Research Fellowship at the National Institutes of Health.

Abbreviations: -dP/dt, Rate of relaxation; +dP/dt, rate of contraction; HCN, hyperpolarization-activated cyclic nucleotide-gated; KO, knockout; PTU, 6-propyl-2-thiouracil; RNase, ribonuclease; SAN, sinoatrial node; SERCA, sarco(endo)plasmic reticulum Ca²⁺ ATPase; TR, thyroid hormone receptor; WT, wild-type.

Received April 24, 2003.

Accepted for publication July 30, 2003.

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