© 2000 American Heart Association, Inc.
Integrative Physiology |
Cardiac Dysfunction Caused by Myocardium-Specific Expression of a Mutant Thyroid Hormone Receptor
From the Thyroid Unit (C.P.-M., E.D.A., M.-E.B., E.M., F.E.W.) and Cardiovascular Division (T.G.H., J.W., J.P.M.), Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass. Dr Pazos-Moura is now at Laboratorio de Fisiologia Endocrina, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, and Dr Moura is at Departamento de Ciencias Fisiologicas, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
Correspondence to Dr Fredric E. Wondisford, Thyroid Unit, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, MA. E-mail fwondisf{at}caregroup.harvard.edu
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Abstract—Thyroid hormone deficiency has profound effects on the cardiovascular system, resulting in decreased cardiac contractility, adrenergic responsiveness, and vascular volume and increased peripheral vascular resistance. To determine the importance of direct cardiac effects in the genesis of hypothyroid cardiac dysfunction, the cardiac myocyte was specifically targeted with a mutant thyroid hormone receptor (TR)-ß (
337T-TR-ß1)
driven by the 
-myosin heavy chain (-MHC) gene promoter. As a
control in these experiments, a wild-type (Wt) TR-ß1 was
also targeted to the heart by using the same promoter. Transgenic mice
expressing the mutant TR displayed an mRNA expression pattern
consistent with cardiac hypothyroidism, even though their
peripheral thyroid hormone levels were normal. When these
animals were rendered hypothyroid or thyrotoxic, mRNA expression of MHC
isoforms remained unchanged in the hearts of the 337T transgenic
animals, in contrast to Wt controls or transgenic animals expressing Wt
TR-ß1, which exhibited the expected changes in
steady-state MHC mRNA levels. Studies in Langendorff heart preparations
from mutant TR-ß1 transgenic animals revealed evidence of
heart failure with a significant reduction in +dP/dT, -dP/dT, and
force-frequency responses compared with values in Wt controls and
transgenic mice overexpressing the Wt TR-ß1. In contrast,
in vivo measures of cardiac performance were similar between Wt
and mutant animals, indicating that the diminished performance
of the mutant transgenic heart in vitro was compensated for by other
mechanisms in vivo. This is the first demonstration indicating that
isolated cardiac hypothyroidism causes cardiac dysfunction in the
absence of changes in the adrenergic or peripheral
vascular system.
Key Words: thyroid hormone resistance • cardiac hypothyroidism • mice
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Introduction |
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Thyroid hormone deficiency has profound effects on cardiovascular function. In the heart, hypothyroidism induces systolic and diastolic dysfunction with reduction in the rate and force of cardiac contraction and a prolongation in cardiac relaxation.1 2 Various cardiac proteins, such as
- and ß-myosin heavy chain (-MHC and ß-MHC,
respectively), sarcoplasmic reticulum
Ca2+-ATPase, and voltage-gated potassium
channels, which are important mediators of cardiac
contractility, are regulated by thyroid
hormone.3 4 5 The promoters of these genes possess thyroid
hormone response elements (TREs), and their expression has been shown
to be regulated by liganded and unliganded thyroid hormone receptors
(TRs). Nongenomic effects of thyroid hormone on cardiac contractility have also been described.6 7 For example, thyroid hormone excess results in significant peripheral vasodilatation, which is believed to be a direct effect and not mediated by nuclear TR action.8 In contrast, reduced capillary red blood cell velocity,9 diminished blood volume,2 10 decreased adrenergic responsiveness,11 and increased peripheral vascular resistance12 occur in hypothyroidism. Therefore, the impaired cardiac function that occurs in hypothyroidism can be ascribed to direct effects on cardiomyocytes as well as to secondary effects on hemodynamic loading. Given the limitations of these in vivo observations, it has been difficult to determine the respective roles of direct versus indirect actions of thyroid hormone on the cardiovascular system.
Mutations in the ß isoform of the TR are associated with the human syndrome of resistance to thyroid hormone (RTH), which is characterized by elevated serum concentrations of thyroid hormone and peripheral tissue insensitivity to thyroid hormone.13 Echocardiographic testing of patients with RTH has revealed evidence of increased cardiac contractility.14 However, these changes are less than would be expected given the degree of elevation of thyroid hormone concentrations. Thus, the blunted response suggests partial resistance of the heart to thyroid hormone in these subjects.14 15 Furthermore, it is unclear to what extent alterations in the peripheral circulation, which occur in response to the increased thyroid hormone levels, are contributing to these changes.
To clarify the specific contribution of TR-mediated thyroid hormone
action on cardiac function, we developed a transgenic mouse model with
cardiac-specific expression of a naturally occurring 337T mutant
TR.16 This mutant receptor is a potent dominant-negative
inhibitor of wild-type (Wt) TR function in vitro and in
vivo.17 18 19 By targeting this receptor selectively to the
hearts of transgenic mice, we were able to induce a hypothyroid
phenotype in the heart in the presence of normal thyroid
hormone serum concentrations and therefore study the direct cardiac
effect of thyroid hormone, independent of effects on the adrenergic and
vascular systems.
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Materials and Methods |
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Transgenic mice overexpressing either Wt or
337T
mutant16 TR-ß1 in the heart were
generated. The murine -MHC promoter was used to direct transgene
expression selectively to cardiac myocytes.20 Wt or mutant
human TR-ß1 cDNA was cloned into a vector
containing 5.5 kb of the murine -MHC promoter and 0.6 kb of the
human growth hormone poly(A) (gift of Dr J. Robbins, University of
Cincinnati, Cincinnati, Ohio). Southern blotting was performed to
identify transgenic animals containing a specific 2.4-kb
BglII fragment with use of a human
TR-ß1 cDNA probe. All studies were approved by the Institutional Animal Care and Use Committee of the Beth Israel Deaconess Medical Center. Transgenic animals have been followed up to 1 year, and no increase in morbidity or mortality was observed in either the MHC-mutant (MHC-Mt) or MHC-Wt strains. Hypothyroidism was induced by feeding animals a 0.15% propylthiouracil-containing diet (Harland Teklad, Co) for 4 weeks. Mice were rendered thyrotoxic by daily intraperitoneal injections of T3 (10 µg/100 g body wt) for 9 days. Blood was obtained from the tail vein for measurements of total T4 and T3 (T4 or T3 kit, ICN Pharmaceuticals).
Total RNA was extracted from heart, liver, kidney, skeletal muscle, and spleen by the phenol/guanidinium thiocyanate method. mRNA levels for mutant and Wt TR-ß1 were determined by ribonuclease protection assay (RPA). Total RNA (20 µg) from each tissue was hybridized with a purified 32P-labeled antisense RNA probe, containing exon 6 and the surrounding intronic sequence from the mouse TR-ß gene, and processed by use of an RPA kit (Ambion Inc). A mouse cyclophilin riboprobe was used to control for RNA quality and quantity.
-MHC and ß-MHC gene expression was also evaluated by RPA with the
use of specific 32P-labeled 3' - and ß-MHC
riboprobes. These probes were obtained by reverse
transcription–polymerase chain reaction of mouse heart mRNA with the
use of primers to the 3' coding sequence and untranslated region of
-MHC and ß-MHC, respectively. The following primers were
used21 : -MHC 5'-GGAAGAGTGAGCGGCGCATCAAGG-3' and
5'-CTGCTGGA-GAGGTTATTCCTCG-3' and ß-MHC
5'-GCCAACACCAACCTGT-CCAAGTTC-3' and
5'-TGCAAAGGCTCCAGGTCTGAGGGC-3', generating a 305- and 206-bp
product for -MHC and ß-MHC, respectively.
Animals were anesthetized with ketamine and xylazine and instrumented, and ECG measurements were performed. A pressure transducer was then inserted and advanced just proximal to the aortic root. Arterial systolic, diastolic, and mean arterial blood pressures were recorded. Subsequently, the pressure catheter was advanced into the left ventricular chamber, where peak left ventricular blood pressure, end-diastolic blood pressure (EDP), peak positive pressure derivative (+dP/dt), and peak negative pressure derivative (-dP/dt) were recorded.
Mice were heparinized, and the heart was rapidly excised and arrested
in ice-cold buffer. The aorta was cannulated and perfused with
Krebs-Henseleit buffer at a rate of 
3 mL/min.22 A
balloon connected to a pressure transducer at one end was inserted
through the mitral annulus into the left ventricular
chamber, and pressure measurements were performed. Indices were
recorded at different pacing frequencies and after the
administration of 0.03 µmol/L isoproterenol. Statistical
differences were assessed by unpaired 2-tailed Student t
test.
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Results |
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Transgene Expression
Wt or mutant (
337T) human TR-ß1
transgenes were specifically targeted to the cardiac myocyte by using
the -MHC gene promoter. Multiple transgenic founder lines were
obtained from both constructs. One line overexpressing the Wt human
TR-ß1 (MHC-Wt, line 6) and 3 lines expressing
the mutant human TR (MHC-Mt, lines 20, 23, and 30) were studied. As
shown in Figure 1
, a mouse TR-ß
exon 6 32P-labeled riboprobe was used to detect
transgene expression in the myocardium and
peripheral tissues. The region of the mouse TR-ß used for
this riboprobe is highly homologous with the same region of human
TR-ß. The left panel of Figure 1 demonstrates TR
overexpression in the heart. The endogenous TR-ß and Wt
TR-ß transgene mRNAs protect the full-length probe.
Endogenous TR-ß mRNA is difficult to appreciate at this
exposure (lane 3), but a 4-fold increase in TR-ß mRNA levels was
noted in the MHC-Wt animal (lane 4). In contrast, mutant TR-ß
expression was detected as a smaller protected fragment because of the
deletion of codon 337 (lanes 5 to 7). The degree of TR-ß
overexpression was similar between the MHC-Wt transgenic animals and 2
of the mutant lines (lines 20 and 23, 4-fold overexpression relative
to endogenous TR-ß mRNA levels). Mutant TR transgene
expression was 60% lower in line 30, as assessed by PhosphorImager
(Molecular Dynamics).
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The right panel of Figure 1
demonstrates that expression
of this transgene was cardiac specific. Data from a line 20 animal are
shown, and similar data exist for the other lines. Mutant TR-ß was
expressed only in the heart (lane 8) and not in the liver (lane 9),
kidney (lane 10), spleen (lane 11), or skeletal muscle (lane 12).
Endogenous mouse TR-ß mRNA was easily detected in the
liver (lane 9) and kidney (lane 10) and, to a lesser extent, in the
heart (lane 8), which is consistent with previously published
observations.23 Animals overexpressing either Wt or mutant
TR-ß1 had thyroid hormone levels that were
indistinguishable from those of Wt animals (Figure 2).
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Analysis of MHC Gene Expression
To determine the effect of TR overexpression on thyroid hormone
signaling in the myocardium, MHC-Wt (line 6) and MHC-Mt
(lines 20 and 23) mice were studied under euthyroid, hypothyroid, and
thyrotoxic conditions. Figure 3 displays
2 RPAs of control (Wt) mice and transgenic mice (MHC-Wt and MHC-Mt)
using either a 3' ß-MHC (top panel) or 3' -MHC (bottom panel)
32P-labeled riboprobe. A
32P-labeled cyclophilin riboprobe was included as
an internal control in both panels and simultaneously
hybridized with the MHC riboprobe. In euthyroid Wt animals, -MHC
mRNA is the predominant MHC species and is even more abundant during
thyrotoxicosis. Conversely, ß-MHC mRNA is the predominant species in
hypothyroid Wt animals. Table 1
displays the results of PhosphorImager (Molecular Dynamics)
analysis of the MHC isoform mRNAs. Note that the
-MHC/ß-MHC ratio in euthyroid Wt animals is 16, reflecting the
higher steady-state -MHC and the much lower ß-MHC mRNA levels at
ambient thyroid hormone levels in adult mice. This ratio increases to
44 in thyrotoxic animals, primarily because of a decrease in ß-MHC
mRNA expression. In contrast, the ratio in hypothyroidism is 0.2,
reflecting a moderate decrease in -MHC mRNA levels and a marked
induction in ß-MHC mRNA levels.
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Transgenic animals overexpressing Wt TR-ß1 in
the heart displayed results qualitatively similar to those in Wt
animals in the various thyroid states studied. Quantitatively, there is
a greater degree of downregulation of ß-MHC expression in
hyperthyroid MHC-Wt mice compared with hyperthyroid control mice,
resulting in a greater -MHC/ß-MHC ratio (Table 1).
Transgenic animals overexpressing the mutant TR-ß exhibit changes in
the expression of MHC isoforms that are consistent with the
pattern associated with hypothyroidism regardless of their serum
thyroid hormone levels. Table 1 indicates that these transgenic
animals exhibit lower levels of -MHC, and the expected induction of
-MHC and repression of ß-MHC expression in thyrotoxicosis is not
seen. Thus, the -MHC/ß-MHC ratios do not change appreciably and
maintain a hypothyroid pattern. These data indicate that overexpression
of the mutant TR-ß1 in the hearts of transgenic
mice induces hypothyroidism in the myocardium regardless of
ambient thyroid hormone levels.
Cardiac Function in MHC-Mt Mice
We next explored the effect of the mutant TR transgene on cardiac
physiology. Figure 4 displays a
representative ECG from a control (left) and a mutant
TR (right) transgenic animal and the mean±SEM ECG intervals from 6 Wt
and 7 mutant transgenic animals (line 20). Note the widened complexes
in the transgenic animals. All time intervals were longer in the
transgenic animals than in the control animals. The PQ and PR
intervals, which roughly represent the
atrioventricular conduction time, are slightly but
significantly prolonged (33%). Importantly, increases were observed
in the time required for ventricular depolarization,
represented by the QRS complex (60% increase) and the ST
interval, which represent the period of time between
depolarization of ventricles and the period of rapid repolarization of
ventricular muscle (79% increase).
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To determine whether cardiac function was impaired in the mutant
transgenic animals, cardiac contractility was measured
in vivo and in isolated perfused heart preparations. Table 2 shows data from isolated heart
preparations of Wt (control) animals and mutant and Wt
TR-overexpressing transgenic animals. Mutant TR transgenic hearts from
line 20 generated less left ventricular pressure and took
longer to do so (+dP/dT) than either control hearts or Wt
TR-overexpressing hearts. Diastolic relaxation was also
impaired, as indicated by a 60% reduction in -dP/dT and an increase
in the time constant of relaxation. Although both positive and negative
dP/dT were impaired in the mutant TR transgenic hearts, the
+dP/dT/-dP/dT ratio suggests that -dP/dT was affected more than
+dP/dT. Similar studies performed in line 30 transgenic mice, which
expressed 60% less of the mutant TR transgene than the other 2 lines,
revealed an intermediate phenotype, with less impairment in
cardiac contractility than that observed in the 2 lines
with higher mutant transgene expression (data not shown). In studies of
paced hearts, mutant TR transgenic hearts exhibited defects in both
+dP/dT (Figure 5A) and -dP/dT (Figure 5B) at all pacing intervals, unlike either Wt or Wt
TR-overexpressing animals. At the highest pacing interval, compared
with Wt animals, MHC-Mt animals displayed a significant increase in EDP
(Figure 5C). In contrast, compared with Wt animals, MHC-Wt
animals had lower EDPs at all pacing intervals.
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In response to isoproterenol administration, isolated hearts of MHC-Mt
mice exhibited percent increases in left ventricular
pressure, +dP/dT, and -dP/dT similar to those in control hearts.
However, the absolute values of these parameters remained
significantly lower in the MHC-Mt animals (Table 3). Compared with control mice, MHC-Wt
mice responded to isoproterenol with a greater percent increase in left
ventricular pressure but a smaller increase in both
positive and negative dP/dT.
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In contrast to the abnormal function in isolated hearts, cardiac
performance in anesthetized mutant TR transgenic
animals was similar to that of control animals, with no
parameter being statistically different between the 2
groups (Table 4). There were trends
toward lower systolic pressure and heart rate and higher EDP in
the mutant TR animals.
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Discussion |
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Myosin, a major protein of cardiac muscle, is composed of light and heavy chains. In euthyroid adult rodents,
-MHC is the
predominant isoform expressed in cardiac myocytes, and the levels of
the ß isoform are negligible. In hypothyroidism, the ß-MHC isoform,
which has lower ATPase activity than the -MHC isoform, becomes the
predominant species.3 The -MHC gene is
transcriptionally regulated by TRs, which bind to a positive TRE
in the promoter of the gene.24 Conversely, ß-MHC gene
expression is negatively regulated by thyroid hormone via mechanisms
that remain unclear.25 Transgenic mice bearing the mutant
TR in the heart revealed a pattern consistent with cardiac
hypothyroidism, with suppression of -MHC and a marked induction of
the ß-MHC isoform. Because circulating levels of thyroid hormones
were normal, these findings are the likely result of dominant-negative
interference of Wt TR function by the mutant TR. The persistence of the
hypothyroid pattern of MHC gene expression in
T3-treated mutant transgenic mice indicates the
presence of profound cardiac RTH. Hypothyroidism resulted in minimal
changes in MHC gene expression in mutant transgenic mice, suggesting
that the induction of ß-MHC and the repression of -MHC are nearly
maximal at ambient thyroid hormone concentrations in euthyroid
transgenic mice (Table 1). These data provide strong evidence of
the role of the TR in regulating MHC gene expression in vivo.
Altered MHC expression may explain, in part, the impaired cardiac
contractility observed in isolated perfused hearts. The
activity of the myosin ATPases determines the rate of formation and
dissolution of actin-myosin crossbridges and, ultimately, the velocity
of muscle contraction. Myosin composed of ß-MHC dimers has a markedly
lower ATPase activity relative to myosin composed of -MHC dimers,
which leads to a decrement in the maximum velocity of contraction of
cardiac muscle.26 It is also likely that impairment of
other cardiac-specific genes regulated by thyroid hormone, such as
sarcoplasmic reticulum Ca2+-ATPase, are likely to
be involved in the cardiac contractile dysfunction observed in mutant
TR transgenic animals. Finally, decreased oxidative
metabolism in the hypothyroid hearts of transgenic mice
might lead to decreased ATP availability. Thus, findings of decreased
cardiac contractility in the isolated hearts of our
mutant TR transgenic mice support similar data obtained in the isolated
perfused hearts of rats with systemic hypothyroidism.2
Our findings are novel compared with the work of Gloss et
al,18 who reported an altered cardiac phenotype in
transgenic mice expressing the 337T-TR-ß1
mutant. In their study, expression of the mutant TR was driven by a
ß-actin promoter, which, in contrast to the present study, is
ubiquitously expressed. Although these animals had apparently normal
thyroid hormone levels, one cannot exclude the possibility that small
differences exist in circulating or local tissue concentrations of
thyroid hormones because of global expression of the mutant TR. Their
animals showed a hypothyroid MHC mRNA expression pattern and a delay in
the contraction and relaxation of isolated papillary muscles without a
change in the maximum active tension. The present study provides
new data on isovolumic contractile performance in isolated
perfused hearts under baseline conditions and in response to changes in
workload. In the present study, we have demonstrated that isolated
cardiac RTH clearly results in global cardiac dysfunction.
The preserved in vivo contractile performance relative to Wt
mice contrasts with the unambiguous demonstration of contractile
dysfunction in isolated perfused hearts. There are a number of possible
explanations for this observation. First, it is possible that
compensatory in vivo mechanisms that ultimately result in improved
cardiac performance exist. One possibility is increased
adrenergic activity in the mutant transgenic mice. Although we did not
directly measure adrenergic activation in the present study, our
observation that administration of isoproterenol increases contractile
performance of the transgenic isolated hearts provides some
evidence that this could be a plausible mechanism. Sympathoadrenal
activation is an important compensatory response in vivo that seeks to
maintain cardiac output in the face of primary ventricular
dysfunction. A second possibility stems from the fact that the
assessment of in vivo cardiac contractility was
performed in anesthetized mice. The effect of
anesthesia is evident in the fact that the heart rates
observed in Wt mice were significantly lower than values obtained in
awake animals.27 Therefore, the cardiodepressant effect of
anesthesia in Wt and transgenic mice could attenuate any
differences that exist. In fact, some of the in vivo measurements
tended to be abnormal in transgenic mice (increased EDP
[P<0.06] and decreased heart rate
[P<0.07]). It is possible that impaired
ventricular performance would be detected if
measurements were made during exercise, which would increase cardiac
work. This is supported by the observation that the isolated perfused
hearts of mutant transgenic animals demonstrated impairment in both
systolic and diastolic function with cardiac pacing
(Figure 5).
Changes in the ECG of mutant TR transgenic animals resemble those found
in hypothyroid patients.28 Prolongation of ECG intervals
indicate reduced velocity of conduction of the action potential
diffusely throughout the contracting myocardial cells. The mechanism
may be related to abnormal ion channel expression, because altered mRNA
levels of voltage-gated potassium channels have been reported in
experimental hypothyroidism.5 Careful analyses of
ECG changes have been performed in transgenic mice lacking
TR-129 and TR-ß and in TR-ß and
TR-1 double-knockout mice.30 The
deletion of TR-ß is associated with increased basal heart rates but
with a blunted heart rate response to
T3.30 In contrast,
TR-1 knockout mice are bradycardic, with heart
rates that are 20% less than heart rates in Wt control mice. Heart
rates were also decreased by 20% in our model, which suggests that the
mutant TR-ß transgene blocked TR-1–mediated
mechanisms that govern heart rate. The prolongation in the QRS complex
of 65% and in the QT interval of 55% (versus control mice) seen in
our transgenic mice is much greater than that reported in
TR-1/ß and TR-1
knockout mice. The difference in these models suggests that
dominant-negative inhibition of thyroid hormone receptor action in the
heart results in a different phenotype than is observed in the
absence of all TRs in the heart. The molecular basis for this
difference may be repression of cardiac gene expression by the mutant
TR versus a lack of thyroid hormone activation in the TR knockout
animals.
The present study indicates that the impairment of thyroid hormone action selectively in the heart leads to left ventricular dysfunction. Our model provides mechanistic insight into the observation of the relative impairment in cardiac contractility seen in many patients with RTH.14 This model has provided a more complete assessment of the role of thyroid hormone deficiency on cardiac function in the absence of peripheral vascular changes that occur in hypothyroidism.
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Acknowledgments |
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This study was supported by National Institutes of Health grants to Dr Abel (DK-02485) and Dr Wondisford (DK-49126 and DK-50564). Drs Pazos-Moura and Moura were recipients of a National Council for Research Development (CNPq) grant from the government of Brazil. Dr Abel was the recipient of a Faculty Development Award from the Robert Wood Johnson Foundation and of an Eleanor and Miles Shore Fellowship (Harvard Medical School).
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Footnotes |
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1 Both authors contributed equally to this work.
Received November 19, 1999; accepted December 15, 1999.
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