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Divisions of Endocrinology and Cardiology, Departments of Medicine and Pediatrics, North Shore-Long Island Jewish Health System and New York University School of Medicine, New York, New York 11030
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2), phospholamban (PLB), and Na+/Ca2+ exchanger (NCX). To further understand the potential cardiac chamber-specific effects of thyroid hormone action, we compared the triiodo-L-thyronine (T3) responsiveness of calcium transporter proteins in atrial versus ventricular tissues. Rats were rendered hypothyroid by ingestion of propylthiouracil, and a subgroup of animals was treated with T3 for 7 days (7 µg/day by constant infusion). Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis. SERCA2 protein significantly decreased by 50% in hypothyroid LV and was normalized by T3 treatment. In contrast, SERCA2 protein in atria was unaltered in the hypothyroid state. PLB protein expression significantly increased by 1.6- and 5-fold in the hypothyroid LV and atria, respectively, and returned to euthyroid levels with T3 treatment. Expression of NCX protein showed a greater response to T3 treatment in atria tissue than in ventricular tissue. Sarcoplasmic reticulum calcium cycling is determined in part by the ratio of SERCA2 to PLB. This ratio was sixfold higher in the atria compared with LV, suggesting that PLB may play a minor role in the regulation of SERCA2 function in normal atria. We conclude that calcium transporter proteins are responsive to thyroid hormone in a chamber-specific manner, with atria showing a greater change in protein content in response to T3. The differential effect on atria may account for the occurrence of atrial rather than ventricular arrhythmias in response to even mild degrees of thyrotoxicosis.
calcium ATPase; sodium/calcium exchanger; phospholamban; myocytes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WELL ESTABLISHED
that thyroid hormone has profound effects on the cardiovascular
system (19). All measures of cardiac contractility
including systolic and diastolic function are augmented in the
hyperthyroid patient and are impaired in hypothyroidism (23). The inotropic effects of
triiodo-L-thyronine (T3) are mediated in part
by its ability to regulate the transcription of genes encoding calcium
transporter proteins of the sarcolemma and the sarcoplasmic reticulum
(SR) as well as specific myofibrillar proteins (10, 17,
25). Contraction of the adult cardiomyocyte is dependent
primarily on Ca2+ release from the SR triggered by
Ca2+ entry via L-type Ca2+ channels during
membrane depolarization, whereas myocyte relaxation during diastole
involves the reuptake of calcium into the SR by a calcium-activated
ATPase [sarco(endo)plasmic reticulum Ca2+-ATPase
(SERCA2)] (2, 20). SERCA2 activity is regulated by phospholamban (PLB), an integral SR membrane protein, which has maximal
inhibitory activity when it is dephosphorylated (12). Reversal of the PLB inhibition of SERCA2 is achieved primarily by
phosphorylation of PLB by cAMP-dependent protein kinase, which is the
primary mechanism by which 
-adrenergic receptor agonists exert
positive inotropic action on the heart (13, 15, 22).
The cardiac functional changes associated with hypothyroidism,
including impaired contractility and calcium cycling with lower calcium
transients (32), are accompanied by a decrease in
expression of SERCA2 and an increase in PLB protein content (10,
17). In experimental animal models, these phenotypic
changes are reversible with T3 treatment (30).
Transgenic animals overexpressing SERCA2 in the heart maintain left
ventricular (LV) contractility when rendered hypothyroid similar to
that achieved with thyroid hormone replacement (9).
Similarly, transgenic mice deficient in PLB expression show increased
contractility and SR Ca2+ uptake, and, when rendered
hypothyroid, cardiac contractility is similar to that in control
wild-type animals (16). Studies by Kranias and colleagues
(15) have demonstrated the importance of the SERCA2-to-PLB
protein ratio in determining cardiomyocyte contractility. Studies by
Holt et al. (10) have shown that the SERCA-to-PLB ratio is
increased in adult cardiac myocytes cultured in 10
8 M
T3 for 48 h primarily as a result of a decrease in PLB
expression. These changes in gene expression were associated with an
improvement in diastolic calcium transients. Studies of SR calcium
uptake in response to thyroid hormone have different effects in atria compared with ventricles (13), which may be explained by
the results in the present study.
The Na+/Ca2+ exchanger (NCX) functions primarily to extrude calcium that enters the myocyte from the extracellular space, but can operate in reverse mode when intracellular sodium is elevated, and has been shown to contribute to contractile function in failing human ventricular myocytes (7, 31). NCX expression has been shown to be increased in various human and animal models of heart failure (29). Thyroid hormone has been suggested to negatively regulate expression of the NCX gene such that the myocardial content of the NCX protein is increased in hypothyroid animal models (3, 5).
In the present study, we examined the differential effects of thyroid
hormone on the expression of NCX, PLB, and SERCA2 in both rat atria and
ventricles. Previously published data have shown that T3
treatment of hypothyroid rats produces an increase in atrial SR
Ca2+ pump function, which lead to a proportionately greater
increase in contractility and relaxation in atria compared with
ventricles (14). Those results are in contrast with the
lack of thyroid hormone regulation of the T3-responsive
-myosin heavy chain (MHC) and Kv1.5 genes in atria compared with
ventricles (27). The present study shows a
chamber-specific effect of T3 on the expression of calcium
transporter proteins in the rat heart.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal protocols. Eight male Sprague-Dawley rats (Charles River Breeding Laboratories; Kingston, NC) weighing 180-200 g were rendered hypothyroid by ingestion of 6-n-propyl-2-thio-uracil (PTU; 4.4 mM) in drinking water for 5 wk. A subgroup of these animals received T3 (Sigma; St. Louis, MO) for the final 7 days of the study (T3 treated). T3 was delivered subcutaneously by constant infusion via a miniosmotic pump (Alza; Palo Alto, CA) set to deliver 7.0 µg T3/day. Five age-matched rats fed ad libitum served as controls. One day before euthanization, the animals were sedated (ketamine-xylazine), and their cardiac function was measured by echocardiography (7.5-MHz probe, Acuson; Mountainview, CA). Ejection fractions (EF) were determined by M-mode analysis, and heart rates were obtained by electrocardiogram as previously described (24).
A separate group of 16 animals was used to study the time course of response of cardiac genes to T3 treatment. Twelve rats were rendered hypothyroid by surgical thyroidectomy (1), and, after 2 wk, nine rats were injected subcutaneously with T3 (10 µg) every 12 h. Three rats were euthanized at each of the following time points: 6, 12, and 24 h after the first T3 injection. At the completion of both study protocols, the hearts were removed, and the atria and LV were separated, immediately frozen in liquid nitrogen, and stored at
70°C until analysis.
Analysis of tissue and myocyte RNA and protein.
Tissues were pulverized using a mortar and pestle in liquid nitrogen
for either protein or RNA analysis. RNA was purified by the acidic
phenol method, and total RNA (5 µg) was resolved by denaturing
agarose gel electrophoresis. Northern blot analysis was used for
quantification of SERCA2 and for - and -MHC isoform-specific mRNAs as previously described (1). Poly(A)+ RNA
was further purified from atrial and LV total RNA using
oligo(dT)-affinity chromatography (1) and analyzed for PLB
mRNA concentration by normalization to glyceraldehyde-3-phosphate
dehydrogenase mRNA in each sample using Northern blot analysis as
previously described (24).
SDS-PAGE and immunoblot analysis. The proteins (5 or 30 µg) were resolved by electrophoresis on either 15% or 10% SDS-polyacrylamide gels for immunoblot analysis of PLB or SERCA2 and NCX, respectively (24). Proteins were electrophoretically transferred onto nitrocellulose paper, and nonspecific binding was blocked by 5% nonfat milk in Tris-buffered saline (TBS). Blots were incubated with one of several monoclonal antibodies: anti-PLB (0.05 mg/ml), anti-SERCA2 (1:500 dilution, Affinity Bioreagents; Golden, CO), and anti-NCX IgM (1:1,000 dilution, Research Diagnostics; Flanders, NJ). The secondary antibody used was horseradish peroxidase-conjugated goat anti-mouse IgG or IgM (1:4,000 dilution, Bio-Rad; Hercules, CA). Protein bands were visualized on X-ray film using chemiluminescent reagents (NEN; Boston, MA) and quantified by densitometric scanning within the linear range using volume analysis (Bio-Rad GS-700 PhosphorImager). Results are expressed as arbitrary densitometric units.
Isolation and culture of cardiac myocytes.
Neonatal rat ventricular and atrial myocytes were isolated from
2-day-old pups by collagenase digestion as previously described (26). Cells were plated at a density of 1.5 × 104/cm2 onto collagen-coated 100-mm dishes in
PC-1 medium (Hycor Biomedical; Portland, ME). After the initial plating
period of 18 h, nonadherent cells were removed by aspiration. The
remaining cells were maintained in DMEM-Ham's F-12 nutrient mixture
(GIBCO-BRL; Gaithersburg, MD) containing an
insulin-transferrin-selenium supplement alone or supplemented with
108 M T3 for 72 h. Cells were harvested
and RNA was extracted for SERCA2 and MHC mRNA analysis as previously
described (26).
Statistical analysis. Results are expressed as means ± SE. An unpaired Student's t-test was used for statistical comparison between groups, and significance was assumed at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals.
Thyroid function testing was performed to confirm the chemical status
of the experimental animals. Serum T3 values showed the
expected decline to <10 ng/dl in animals that were rendered hypothyroid by PTU ingestion, whereas in the T3-treated
group serum T3 was 10-fold higher than control values
(Table 1). Because the
T3-treated animals continued to ingest PTU, the serum total L-thyroxine values were similar to the hypothyroid group,
and both were significantly lower than control (Table 1).
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Western blot analysis of SERCA2, PLB, and NCX.
As shown in the representative Western blot in Fig.
1, changes in thyroid hormone status
produced significant changes in expression of calcium transporter
proteins. Quantitative analysis of these proteins is shown graphically
in Fig. 2, A-C. The
expression of SERCA2 protein was decreased by 50% in the ventricles of
hypothyroid rats, with no change observed in the atria (Fig.
2A). In contrast, T3 treatment increased SERCA2
protein content in both ventricles and atria, resulting in a return to
control values in ventricles and an increase of 190% in the atria of
T3-treated rats compared with controls.
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Time course of T3 effects on SERCA2, PLB, and -MHC
mRNA expression.
Quantification of SERCA2 and -MHC mRNA expression in atria and
ventricles in response to thyroid hormone by Northern blot analysis is
shown in Fig. 3, A and
B, respectively. SERCA2 mRNA content in both atria and
ventricles was decreased in hypothyroid animals by 60-80%
compared with the control condition. Expression in both chambers was
increased within 24 h of T3 treatment, with expression
in the LV increased significantly above control levels to 154% (Fig.
3A). The atrial SERCA2 mRNA values are discordant with its
protein content in the hypothyroid condition in that mRNA expression
was significantly lower in the absence of thyroid hormone, whereas
SERCA2 protein was unaltered. However, both protein and mRNA increased
significantly in response to high-dose T3 treatment.
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-MHC mRNA in atria was not suppressed by
hypothyroidism as it was in the ventricle (Fig. 3B), and
atrial expression of -MHC was not detected (data not shown). In
contrast, expression of -MHC mRNA was increased de novo in LV of
hypothyroid rats at a time when -MHC mRNA was completely suppressed
(Fig. 3B), similar to that previously published (5, 8,
18). T3 treatment of the hypothyroid animals
returned -MHC mRNA levels to control values in ventricles within
24 h, whereas -MHC mRNA concentration in atria was increased
significantly to 180% of control levels.
Expression of PLB mRNA in the ventricles was negatively regulated by
thyroid status with a significant increase in hypothyroid animals to
178% of control and a subsequent decrease to control levels within
24 h of T3 treatment (Table
3). These data are concordant with PLB
protein expression in LV (Fig. 2). In contrast, PLB mRNA expression in
atria was unaltered by thyroid hormone status (Table 3), whereas atrial
PLB protein significantly increased in the hypothyroid animal and
subsequently decreased to control levels by T3 treatment
(Fig. 2). These data support a cardiac chamber-specific responsiveness
to T3 both at the transcriptional and
posttranscriptional levels of gene expression.
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Effect of T3 on cultured neonatal rat myocytes.
Similar to that determined in the intact heart, cultured neonatal
atrial myocytes expressed only -MHC mRNA with no detectable -MHC
even in the absence of T3. In contrast, neonatal
ventricular myocytes expressed both MHC mRNA isoforms, with -MHC
mRNA ~70% of the total MHC RNA content. When the myocytes were
cultured in media containing T3, the -MHC mRNA content
was increased by 143% and 130% in ventricular and atrial myocytes,
respectively, compared with medium without T3 (Fig.
4). The amount of -MHC mRNA in
ventricular myocytes remained unchanged at ~30% of the total MHC
mRNA (data not shown). Expression of SERCA2 mRNA was increased in
response to T3 in both atrial and ventricular myocyte cultures to a similar extent (Fig. 4). These data support a direct effect of T3 on the cardiac myocyte independent of its
peripheral hemodynamic effects that affect the heart indirectly, as we
previously characterized (26, 28, 33).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The effects of thyroid hormone on cardiac contractile function
have been well recognized in experimental animal models and in human
thyroid disease (19). The molecular mechanism by which thyroid hormone elicits these effects occurs primarily at the cell
nucleus by binding to specific nuclear receptors and activating or
repressing transcription of target genes (4, 6). Of the numerous cardiac genes regulated by thyroid hormone, those encoding calcium transport and regulatory proteins including SERCA2, PLB, and
NCX are potentially responsible for the observed hypercontractile state
of the myocardium in the hyperthyroid condition (23, 30). This observation has been studied in the rodent model of thyroid dysfunction in which regulation of ventricular genes has been extensively examined. The concept that the atrial myocyte was less
responsive to thyroid hormone than the ventricular myocyte is derived
primarily from early studies (11) of MHC isoform genes. In
the adult rat ventricle, expression of -MHC mRNA predominates in the
euthyroid and hyperthyroid states, whereas -MHC mRNA is expressed de
novo in hypothyroidism, and -MHC is completely repressed (1,
11). In contrast, expression of these two isoforms in atria has been shown not to be regulated by thyroid hormone such that
-MHC mRNA is the primary isoform expressed under both hyper- and
hypothyroid conditions (11). The data in the present study confirm those early observations showing that MHC isoform expression at
the mRNA level was not significantly decreased by the absence of
T3 in atria as it was in the ventricles; however, atrial
-MHC mRNA expression could be increased in response to
T3 treatment (Fig. 3B).
The most striking observation in the present study is the threefold greater response of PLB protein expression to thyroid hormone in atria compared with that observed in ventricles. As shown in this study and in other reports (14, 21), the content of PLB protein in atria is less than that in ventricles, whereas the expression of SERCA2 protein in both chambers is comparable. The ratio of SERCA2 to PLB is therefore sixfold higher in atria, suggesting that SERCA2 activity and the resulting calcium-cycling activity may not be regulated to the same extent by PLB in atria as it is in ventricles (Table 2). The present observation that T3 treatment increased the SERCA2-to-PLB ratio 12-fold in atria and only 6-fold in ventricles (Table 2) may explain the clinical observation that atrial arrhythmias are a common occurrence in hyperthyroid patients, whereas ventricular rhythm abnormalities are rare (19).
The expression of NCX protein in the atrium also appears to be negatively regulated by thyroid hormone, whereas it is not in the ventricle (Fig. 2C). The ratio of NCX to SERCA2 was shown to be similarly increased by 1.6-fold in LV and atria in the hypothyroid animal (Table 2), suggesting a greater role for extracellular calcium in contractile function in both chambers in the hypothyroid condition. The increased role of NCX in calcium transients, thought in part to compensate for an impairment of SR function, in other cardiac disease states such as heart failure has been reported (7). The present data suggests that this may be the case for atrial function in the hypothyroid condition and appears to explain the data reported by Kaasik et al. (14), who showed that thyroid hormone elicited a greater stimulation of the SR calcium pump in atria compared with ventricles.
The present data showing discordant expression between protein and mRNA for SERCA2 and PLB gene products supports the roles of both transcription and posttranscriptional mechanisms in modulating cardiac gene expression. Phenotypic changes in the myocyte in response to various stimuli including T3 and hemodynamics appear to depend on these processes to varying degrees, highlighting the numerous mechanisms available to the myocyte in maintaining optimal contractile function.
In summary, we conclude that calcium transporter proteins are responsive to thyroid hormone in a chamber-specific manner, with atria showing a greater responsiveness with T3 treatment. The change in the expression of these proteins in response to thyroid hormone might in part be responsible for the improvement in LV function seen with thyroid hormone treatment of hypothyroidism with differential effects on atria and ventricles.
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ACKNOWLEDGEMENTS |
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This study was supported by the Hutzler Fund and by National Heart, Lung, and Blood Institute Grants HL-56804 (to K. Ojamaa) and HL-58849 (to I. Klein).
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. Ojamaa, Div. of Endocrinology, North Shore Univ. Hosp., 300 Community Dr., Manhasset, NY 11030 (E-mail: kojamaa{at}nshs.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 20 December 2000; accepted in final form 18 June 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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 Y. Ohga, S. Sakata, C. Takenaka, T. Abe, T. Tsuji, S. Taniguchi, and M. Takaki Cardiac dysfunction in terms of left ventricular mechanical work and energetics in hypothyroid rats Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H631 - H641. [Abstract] [Full Text] [PDF]
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P < 0.05 vs. other atrial values. LV, left
ventricle.
