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Endocrinology Vol. 148, No. 7 3477-3484
Copyright © 2007 by The Endocrine Society

Rapamycin Prevents Thyroid Hormone-Induced Cardiac Hypertrophy

James A. Kuzman, Timothy D. O’Connell and A. Martin Gerdes

Sanford Research/University of South Dakota, Sanford School of Medicine, Cardiovascular Research Institute, Sioux Falls, South Dakota 57105

Address all correspondence and requests for reprints to: A. Martin Gerdes, Ph.D., Cardiovascular Research Institute, 1100 East 21st Street, Suite 700, Sioux Falls, South Dakota 57105. E-mail: mgerdes{at}usd.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Although THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or whether it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures treated with THs to test whether mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T4 for 3 d, 1 wk, 2 wk, or 1 month with either placebo, T4 (50 µg/100 g body weight·d), rapamycin (200 µg/100 g body weight·d) or T4/rapamycin by sc slow-release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THYROID HORMONES (THs) (T3 and T4) have many effects on the heart including the induction of cardiac hypertrophy, although little is known about the mechanism. THs exert many of their effects through binding to nuclear receptors that activate or suppress gene transcription. Contrary to the classical genomic mechanism of THs, recent studies suggest that THs also act through a nongenomic mechanism by binding to a membrane receptor to activate signaling (1). Signal transduction pathways such as phosphatidylinositol 3-kinase/AKT and MAPK have been implicated in the effects of TH such as angiogenesis (2) and cardiac hypertrophy (3). Recently, we showed that T3 activates AKT in neonatal cardiomyocytes (NCMs), which prevented serum starvation-induced cell death. Overall, it is quite clear that THs activate signal transduction pathways in NCMs that are responsible for carrying out some of the hormone effects. However, less is known about the role of signal transduction pathways in the effects of TH in vivo.

Interestingly, TH-induced hypertrophy is phenotypically similar to the physiological hypertrophy mediated by AKT signaling, suggesting overlapping mechanisms (4). In a previous study done in our lab, we found that T4 activates signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] (5). Because activation of signal transduction pathways is often a transient event, a comprehensive time course study is needed to more completely understand what pathways are activated at different time points. Also, if the AKT signaling pathway contributes to the effects of THs on the heart, blocking this pathway should attenuate some of the effects such as hypertrophy and increased contractility.

Although mTOR signaling has been implicated in TH-induced myocyte hypertrophy (3), the role of p70 S6 kinase and mTOR in vivo has not been investigated. It has been shown that mTOR is involved in cardiac hypertrophy due to pressure overload (6, 7). Because increased protein synthesis is a hallmark of hypertrophy, activation of mTOR might be an important pathway through which THs induce hypertrophy. Here, we present evidence that rapamycin inhibits cardiac myocyte hypertrophy, thereby implicating mTOR/S6 kinase signaling in TH-induced cardiac hypertrophy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental design
Two-month-old C57BL/6J female mice were obtained from Jackson Laboratories (Bar Harbor, ME). The mice were randomly separated into different treatment groups. The different treatments included placebo, rapamycin (200 µg/100 g body weight·d; Wyeth Pharmaceuticals, Cambridge, MA), T4 (50 µg/100 g body weight·d; Sigma Chemical Co., St. Louis, MO), or T4 plus rapamycin. Each treatment was administered for 3, 7, 14, or 30 d by slow-release implantable pellets obtained from Innovative Research (Sarasota, FL). The hearts were removed, blotted, weighed, and either snap-frozen or used for isolation of myocytes via aortic perfusion with collagenase. All procedures in this study were approved by the University of South Dakota Animal Care and Use Committee and followed institutional guidelines for animals.

Western blotting
Frozen whole left ventricular tissue was powdered in liquid nitrogen and RIPA buffer with protease inhibitor cocktail (EMD Biosciences Inc., San Diego, CA), phosphatase cocktail inhibitor (Sigma), and 1 mM phenylmethylsulfonyl fluoride. Each sample was incubated at 4 C for 15 min and sonicated to completely homogenize the tissue. Cell lysates were centrifuged at 12,000 x g for 15 min. The supernatant was collected and stored in aliquots at –80 C. Protein concentrations of the cell lysates were determined by a bicinchoninic acid protein assay. Samples were then mixed with Laemmli buffer containing 5% ß-mercaptoethanol and loaded onto SDS-PAGE gels. Proteins were transferred to polyvinylidene difluoride membranes, and blots were probed with antibodies specific to phospho-p70 S6 kinase (Ser 421/424), phospho-p70 S6 kinase (Thr 389), total p70 S6 kinase, phospho-S6 ribosomal protein (Ser 235/236), total S6 ribosomal protein, phospho-ERK (Thr 202/Tyr 204), total ERK, phospho-AKT (Ser 473), phospho-AKT (Thr 308), and total AKT (Cell Signaling Technology, Beverly, MA). Bands were visualized using chemiluminescence (Pierce, Rockford, IL), and relevant band intensities were quantified using a Versadoc Imaging System model 3000 (Bio-Rad Laboratories, Inc., Hercules, CA).

Myocyte isolation and cell volume measurements
Adult mouse myocytes were isolated as described by O’Connell et al. (8). Myocytes were fixed in 2% glutaraldehyde, and volume was measured using a Coulter Channelyzer as described in detail before (9).

Neonatal myocyte cultures
Neonatal myocytes were isolated from 0- to 2-d-old rat pups using a kit from Worthington Biochemical Corp. (Lakewood, NJ). The cells were then seeded in 60-mm (1.5 x 106 cells) dishes for Western blot analysis. Cells were cultured in 10% serum for 24 h after isolation. Serum-containing media was then removed, and cells were cultured in serum-free media for 24 h. T3 (100 nM), rapamycin (1 nM), or a combination was then added to the media, and the cells were cultured for the respective times listed in the results. Cells were harvested in RIPA buffer or trypsinized for cell volume measurements using a Coulter Channelyzer.

Data analysis
All data are expressed as means ± SD. One-way ANOVA or t tests were used to detect significant differences between groups. The Student-Newman-Keuls test was used as a post hoc test. A P value ≤ 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of T4 and rapamycin on hemodynamics
T4 treatment predictably increased heart rate at 3 and 7 d (Table 1Go). However, there was not a significant difference in heart rate at the 14- or 30-d time points (Table 1Go). At 2 wk, +dP/dT (maximum rate of pressure increase) was significantly increased in the T4/rapamycin group compared with placebo, and –dP/dT (maximum rate of pressure decrease) was significantly elevated in T4 and T4/rapamycin compared with control at 2 wk. There were no significant changes in hemodynamic measurements after 1 month of treatment.


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  		TABLE 1. Effects of T4 and rapamycin on hemodynamics

 
Activation of signal transduction pathways at different time points
Three days.
We measured the expression and phosphorylation of members of the AKT signaling pathways at each time point. At 3 d, phosphorylation of AKT (Ser473) and S6 kinase (Thr389) were significantly increased (Fig. 1Go). T4 also increased expression of S6 ribosomal protein, which is downstream of S6 kinase. Because the total and phosphorylated forms were increased in proportion, there was not a significant difference in the phospho/total ratio of S6 ribosomal protein. There were no changes in the phosphorylation of ERK.


Figure 1
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  		FIG. 1. Western blots from mice treated with T4 for 3 d. Densitometry is expressed as a ratio of phosphorylated to total protein. *, P < 0.05 compared with placebo.

 
Seven days.
After 7 d of treatment, phosphorylation of AKT (Ser473) returned to relatively normal levels (Fig. 2Go). However, phosphorylation of AKT (Thr308) was significantly increased. Molecules downstream of AKT were not significantly changed, although there was a trend for increased phosphorylation of S6K (Thr389). Also, the expression of total S6 ribosomal protein remained increased at this time point. Again, there was no change in the phosphorylation of ERK.


Figure 2
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  		FIG. 2. Western blots from mice treated with T4 for 7 d. Densitometry is expressed as a ratio of phosphorylated to total protein. *, P < 0.05 compared with placebo.

 
Fourteen days.
After 14 d of treatment, there was a significant increase in the phosphorylation of AKT 308 with rapamycin treatment alone (Fig. 3Go). Again, there was a trend for phosphorylation of S6K, but the changes were not significant. Although T4 treatment did not increase the phosphorylation of S6, there was a reduction in the phosphorylated levels with rapamycin. Also, expression of total S6 ribosomal protein was increased with T4 treatment. This increase in S6 expression was prevented by rapamycin.


Figure 3
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  		FIG. 3. Western blots from mice treated with rapamycin (RAP), T4, or T4/RAP for 14 d. Densitometry is expressed as a ratio of phosphorylated to total protein. *, P < 0.05 compared with placebo; {dagger}, P < 0.05 compared with T4.

 
Thirty days.
T4 increased the phosphorylation of S6 kinase and S6 ribosomal protein (Fig. 4Go). This effect was completely blocked in mice treated with both T4 and rapamycin. There was no difference in phosphorylated AKT with T4 treatment. However, there was a significant increase in phosphorylated ERK with T4 treatment that was unaffected by rapamycin.


Figure 4
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  		FIG. 4. Western blots from mice treated with rapamycin (RAP), T4, and T4/RAP for 30 d. Densitometry is expressed as a ratio of phosphorylated to total protein. *, P < 0.05 compared with placebo; {dagger}, P < 0.05 compared with T4.

 
Rapamycin prevented T4-induced myocyte hypertrophy
At 2 wk, heart weight was 32% greater in the T4 group compared with placebo (Table 2Go). Heart weight in the T4/rapamycin group was significantly lower than the T4 group, suggesting rapamycin attenuated T4-induced hypertrophy. Although the heart weight in the T4/rapamycin group was significantly elevated compared with the placebo group, there was also a significant increase in body weight with T4 treatment. Comparison of heart weight/body weight between placebo and T4/rapamycin suggests that rapamycin completely prevented the cardiac growth induced by T4.


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  		TABLE 2. Effects of T4 and rapamycin on body and heart weight

 
Similar results were obtained at the 1-month time point (Table 2Go). T4 significantly increased heart weight compared with placebo (27%), which was completely prevented by rapamycin. To confirm that rapamycin prevented myocyte hypertrophy, we measured cell volume at the 1-month time point (Fig. 5Go). Percent changes in cell volume were virtually identical to changes in heart weight, confirming that rapamycin prevented T4-induced myocyte hypertrophy.


Figure 5
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  		FIG. 5. Myocyte volume measurements from mice treated with T4 for 30 d. *, P < 0.05 compared with placebo.

 
Effects of TH in vitro
Treatment with T3 for 15 min, 60 min, and 3 h did not have any effect on the levels of phosphorylated S6 ribosomal protein, which is downstream of both AKT and S6 kinase (Fig. 6Go). However, there was increased phosphorylation of S6 ribosomal protein at 24 h. At all time points, rapamycin reduced phosphorylation of S6 ribosomal protein, showing inhibition of this pathway.


Figure 6
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  		FIG. 6. Western blots measuring phosphorylation of S6 ribosomal protein from NCM extracts. NCMs were treated with T3, rapamycin (RAP), or T3/rapamycin.

 
When NCMs were treated with T3 for 4 d, there was an increase in the phosphorylation of the AKT pathway (Fig. 7Go). Phosphorylation of AKT, S6 kinase, and S6 ribosomal protein was found to be increased in all. Rapamycin blocked T3-induced phosphorylation of S6 kinase and S6 ribosomal protein. However, rapamycin did not decrease T3-induced phosphorylation of AKT. In fact, phosphorylation of AKT was further increased by rapamycin treatment. ERK signaling was not affected by any of the treatments.


Figure 7
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  		FIG. 7. Western blots for different components of the AKT signal transduction pathway in NCM extracts. NCMs were treated with T3 or T3/rapamycin.

 
NCMs treated with T3 for 4 d were also used to confirm that the effect of rapamycin on T3-induced hypertrophy was direct rather than systemic. Volume of NCMs was measured with a Coulter Channelyzer after cell isolation by trypsinization. Cell volumes of T3-treated myocytes were almost identical to cells cultured in media supplemented with 10% serum (Fig. 8Go). When T3 treatment was combined with rapamycin, the increase in cell volume was attenuated. This confirms that T3 stimulates myocyte hypertrophy directly rather than systemically, and this effect is blocked by rapamycin.


Figure 8
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  		FIG. 8. NCM volume measurements from cells treated for 4 d. *, P < 0.05 compared with cells cultured with 10% serum; {dagger}, P < 0.05 compared with cells treated with T3.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We present a novel mechanism through which THs induce cardiac hypertrophy in vivo. Our data suggest that mTOR activity is required for TH-induced hypertrophy. In this study, T4 treatment affects AKT signaling in a temporal manner. The phosphorylation/activation of AKT/S6 kinase correlates with increased translation, which is a hallmark of cardiac hypertrophy (10). Interestingly, T4 also seemed to increase the expression of S6 ribosomal protein at certain time points. The principal finding of this study was that rapamycin blocked the effects of THs on mTOR/AKT signaling, which prevented TH-induced hypertrophy.

In this study, the selected dose was intended to induce hyperthyroidism in the mice. However, significant increases in heart rate were observed only at the 3- and 7-d time points, although there was a trend for an increase at the other time points. Also, T4 treatment did not have much of an effect on dP/dT except for an increase in the T4/rapamycin group at 2 wk. The modest changes in heart rate and contractility from T4 treatment likely reflect the fact that mice already have high sympathetic and low parasympathetic activity. Consequently, one would not expect these changes to be as pronounced as in larger species with lower native heart rates.

T3 clearly increased AKT signaling in vitro. These data also showed that T3 affected signaling only at later time points between 3 and 24 h. Activation of these pathways is further increased after 4 d of treatment. These data are very similar to data we showed in a previous study (11) and suggest that the effect of T3 on signal transduction is delayed in action. This suggests that the mechanism of activating AKT signaling is mediated by a genomic mechanism rather than a nongenomic mechanism. However, the exact mechanism by which TH activates AKT signaling cannot be inferred and was not a major goal of this study.

The data presented in this study clearly show that T4 activates AKT signaling, although activation of some molecules is only transient. T4 increased AKT phosphorylation after 3 d of treatment, and phosphorylation levels were reduced at some point thereafter. Although the phosphorylation of AKT was not increased after 1 month of T4 treatment, an AKT-mediated mechanism for the observed increases in mTOR/S6 kinase cannot be excluded. T4 treatment also increased expression of S6 ribosomal protein. This increase in S6 expression was also reduced by rapamycin treatment. S6 ribosomal protein increases translation of the 5'-terminal oligopyrimidine mRNAs (12). This subset of mRNAs includes those for the cytoplasmic ribosomal proteins and other components of the translational machinery such as elongation factors. Therefore, increased expression and activity of S6 ribosomal protein could also contribute to growth-promoting effects of THs. It seems that both activation of signaling pathways as well as up-regulation of signaling proteins may contribute to the effect of THs on cardiac growth.

Rapamycin has also been shown to promote other effects on cardiomyocytes. Rapamycin binds to 12-kDa FK506-binding protein (FKBP12.6), which interacts with the ryanodine receptor (RyR) to control calcium transients. The interaction of FKBP12.6 and RyR stabilizes the RyR and prevents aberrant release of calcium during the resting phase of the cardiac cycle. Dissociation of FKBP12.6 increases the probability of sarcoplasmic reticulum calcium channels being open and therefore can increase calcium availability and cardiac contractility. It has been shown that rapamycin increases calcium cycling in mouse myocytes (13). However, in a study done by Schoffstall et al. (14), they concluded that the antihypertrophic effect of rapamycin is not mediated through direct effects on myofilament contractility. In addition, we did not observe any significant differences in cardiac function with the treatment of rapamycin in this study. Although it is unlikely, we cannot rule out the possibility that the antihypertrophic effect of rapamycin is partly mediated by a mechanism other than control of protein translation signaling pathways.

Surprisingly, the mechanism of how TH induces cardiac hypertrophy is not well understood. There have been studies that show TH can induce hypertrophy directly in cultured cardiomyocytes and indirectly through alteration in loading conditions of the heart. It is well established that TH has prominent effects on cardiac physiology that could result in compensatory chamber remodeling. It was previously shown that hearts heterotopically transplanted into rats that were treated with THs did not undergo hypertrophy (15, 16). These hearts were exposed to THs in the absence of loading conditions, suggesting that TH-induced hypertrophy is mediated through increased load. However, studies have also shown that T3 can induce hypertrophy in cultured cardiomyocytes, suggesting a direct hypertrophic effect (17, 18). Cardiac hypertrophy is likely due to a combination of both direct and indirect mechanisms. In this study, we show that TH stimulates myocyte hypertrophy both in vitro and in vivo, and this effect is blocked by rapamycin. This confirms that rapamycin blocks the direct effect of THs on myocyte hypertrophy.

Another interesting finding in this study was increased phosphorylation of ERK at the 1-month treatment time point. ERK has been implicated in mediating some of the effects of THs such as myocyte hypertrophy (3, 19) and angiogenesis (1). Many studies have shown that THs can cause nongenomic activation of ERK, which contributes to the effects of TH. In this study, we did not see early activation of ERK. However, after 1 month of treatment, the phosphorylation of ERK is significantly increased. Overall, this study suggests that AKT is most likely important in many of the early effects of THs, whereas ERK may contribute to some of the late effects of THs. It is clear that THs can activate multiple signaling pathways; however, it will require more studies to further understand the timing and interaction of these pathways in promoting effects on the heart.

There are many possible mechanisms through which TH exerts the effects explained in this study. Bergh et al. (1) showed that T4 can bind to {alpha}vß3-integrin heterodimer and activate ERK. Another study recently done by Kenessey and Ojamaa (3) suggests that phosphatidylinositol 3-kinase is directly activated by the T3/TH receptor-{alpha} complex. Alternatively, THs might stimulate the production and release of other growth factors that act in a paracrine manner to bind to membrane receptors and activate downstream signaling pathways. This is supported by our results showing that T3 activated AKT at later time points only in vitro, suggesting the effect is mediated through a genomic rather than a nongenomic mechanism. Although the mechanisms by which TH activates AKT signaling are not yet entirely clear, this study shows mTOR/AKT signaling is necessary for TH-induced cardiac hypertrophy.


   Acknowledgments
 
We thank Rebecca Redetzke and Yuan Huang for their technical assistance.


   Footnotes
 
These studies were supported by Grants HL 62459 and P20 RR017662 from the National Institutes of Health, American Heart Association Grant 04353382, and the South Dakota 2010 Initiative Research Center Grant. Sanford Research/USD is a partnership between the Sanford School of Medicine at the University of South Dakota and Sanford Health (formerly Sioux Valley Hospital and Health Systems) in Sioux Falls.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 29, 2007

Abbreviations: FKBP12.6, 12-kDa FK506-binding protein; NCM, neonatal cardiomyocyte; RyR, ryanodine receptor; TH, thyroid hormone.

Received January 24, 2007.

Accepted for publication March 21, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis PJ 2005 Integrin {alpha}Vß3 contains a cell surface receptor site for thyroid hormone that is linked to activation of MAPK and induction of angiogenesis. Endocrinology 146:2864–2871[Abstract/Free Full Text]
  2. Davis FB, Mousa SA, O’Connor L, Mohamed S, Lin HY, Cao HJ, Davis PJ 2004 Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ Res 94:1500–1506[Abstract/Free Full Text]
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  7. Shioi T, McMullen JR, Tarnavski O, Converso K, Sherwood MC, Manning WJ, Izumo S 2003 Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation 107:1664–16670[Abstract/Free Full Text]
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