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Am J Physiol Heart Circ Physiol 281: H1690-H1696, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 4, H1690-H1696, October 2001

Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles

Rajesh Shenoy, Irwin Klein, and Kaie Ojamaa

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


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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 beta -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 alpha -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.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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 alpha - and beta -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).

For protein analysis, the pulverized frozen LV tissue (~200 mg) was homogenized using a Potter-Elvehjem apparatus in 10 volumes of buffer containing 30 mM Tris · HCl (pH 7.6), 2 mM EDTA, 0.6 M NaCl, protease inhibitors (10 µg/ml each of leupeptin, aprotinin, and antipain and 2.5 µg/ml benzamidine), 1 mM phenylmethylsulfonyl fluoride, and phosphatase inhibitor mixture (Sigma) (24). Frozen atrial samples (~30 mg) were homogenized in 10 volumes of buffer using a 7-ml dounce apparatus. The resulting homogenates were extracted with 0.5% Triton X-100 on ice for 30 min and then diluted with 0.1 M NaCl to precipitate the myofibrillar proteins. After centrifugation at 10,000 g for 20 min at 4°C, the supernatant (10S) was retained and protein was determined by the Lowry method. Samples were denatured in Laemmli buffer by heating to 30°C (for PLB) or to 100°C (for SERCA2 and NCX analysis) before resolution by electrophoresis.

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 10-8 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.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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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  		Table 1.   Effects of thyroid hormone status on cardiac weight and function

Hypothyroid animals showed significant decreases in body weight and LV and right ventricular (RV) weights after 5 wk of treatment such that the heart weight-to-body weight ratio was reduced by 12%, whereas the LV weight was reduced by 38% (Table 1). T3 treatment of the hypothyroid rats for 1 wk significantly increased LV weight by 48% compared with the hypothyroid group, with no significant effect on body weight. The ratios of both LV and RV weights to body weights were significantly higher in the T3-treated group compared with either the control or hypothyroid groups, similar to those previously reported (24).

Measurements of the EF by two-dimensional echocardiography showed a significant decrease of 25% in the hypothyroid group compared with controls. After 1 wk of T3 treatment, there was significant increase in the EF of hypothyroid animals from 66 ± 3% to 81 ± 1% (Table 1), as previously published (24).

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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  		Fig. 1.   Western blots showing the effects of thyroid state on the expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2), phospholamban (PLB), and Na+/Ca2+ exchanger (NCX) proteins in atria (A) and ventricles (V) in control, hypothyroid, and triiodo-L-thyronine (T3)-treated rats. The approximate molecular mass of the proteins (in kDa) are indicated.



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  		Fig. 2.   Graphic analysis of the Western blots shown in Fig. 1 for SERCA2 (A), PLB (B), and NCX (C) proteins (in densitometric units/mg protein) in control (C), hypothyroid (Hypo), and T3-treated (+T3) animals; n = 4 rats/group. *P < 0.05.

PLB expression in response to thyroid hormone was opposite to that of SERCA2. PLB was significantly increased in both atria and ventricles in hypothyroid animals, with a 5-fold increase in atria and a 1.6-fold increase in LV (Fig. 2B). T3 treatment of hypothyroid animals significantly decreased PLB to control euthyroid values in both atria and ventricles. The content of PLB in atria under euthyroid conditions was 20% of that in LV (P < 0.05). This chamber- and gene-specific response to thyroid hormone was further evident when these two proteins were expressed as a ratio of SERCA2 to PLB (Table 2). The SERCA2-to-PLB ratio in the hypothyroid group decreased to 26% of euthyroid control values in both atria and ventricles, whereas T3 treatment produced a significantly greater increase (10-fold) in atria compared with the 5-fold increase in ventricles.

                              
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  		Table 2.   Calcium transporter protein quantitation of sarcoplasmic reticulum proteins

The sarcolemmal NCX protein was increased by 1.7-fold in atria under hypothyroid conditions but was unchanged in LV (Fig. 2C). When NCX expression was expressed as a function of the SR protein SERCA2, the ratio NCX to SERCA2 was increased in hypothyroid animals compared with controls and was restored to control values with T3 treatment in both cardiac chambers (Table 2). The ratio of these proteins appears to be similar in atria and ventricles, with a similar response to thyroid hormone in the two chambers.

Time course of T3 effects on SERCA2, PLB, and alpha -MHC mRNA expression. Quantification of SERCA2 and alpha -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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  		Fig. 3.   Expression of SERCA2 mRNA after T3 treatment of hypothyroid animals. C, euthyroid control animals; H, hypothyroid (thyroidectomized) animals. T3 treatment was evaluated after 6, 12, and 24 h after the first T3 injection. Northern blot analysis of SERCA2 mRNA (A) and alpha -myosin heavy chain (MHC) mRNA (B) in rat atria and ventricles was normalized to 18S rRNA. *P < 0.05 vs. control; Psi P < 0.05 vs. other atrial values. LV, left ventricle.

Expression of alpha -MHC mRNA in atria was not suppressed by hypothyroidism as it was in the ventricle (Fig. 3B), and atrial expression of beta -MHC was not detected (data not shown). In contrast, expression of beta -MHC mRNA was increased de novo in LV of hypothyroid rats at a time when alpha -MHC mRNA was completely suppressed (Fig. 3B), similar to that previously published (5, 8, 18). T3 treatment of the hypothyroid animals returned alpha -MHC mRNA levels to control values in ventricles within 24 h, whereas alpha -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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  		Table 3.   PLB mRNA content in response to thyroid hormone status

Effect of T3 on cultured neonatal rat myocytes. Similar to that determined in the intact heart, cultured neonatal atrial myocytes expressed only alpha -MHC mRNA with no detectable beta -MHC even in the absence of T3. In contrast, neonatal ventricular myocytes expressed both MHC mRNA isoforms, with alpha -MHC mRNA ~70% of the total MHC RNA content. When the myocytes were cultured in media containing T3, the alpha -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 beta -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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  		Fig. 4.   Effects of T3 on alpha -MHC and SERCA2 mRNA content in cultured neonatal rat ventricular and atrial myocytes determined by Northern blot analysis and normalized for 18S rRNA. Values for +T3 (10-8 M) conditions are expressed as a percentage of control values from myocytes cultured in medium deficient in T3 (-T3). Values are means ± SE of 4 or 5 myocyte cultures. *P < 0.05 vs. equivalent control -T3 culture.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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 alpha -MHC mRNA predominates in the euthyroid and hyperthyroid states, whereas beta -MHC mRNA is expressed de novo in hypothyroidism, and alpha -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 alpha -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 alpha -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.


    ACKNOWLEDGEMENTS

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).


    FOOTNOTES

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.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 281(4):H1690-H1696
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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