(The FASEB Journal. 2006;20:1090-1096.)
© 2006 FASEB
Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart
Peter Razeghi*,
Malgorzata Buksinska-Lisik*,
Nanthini Palanichamy
,
Stanislaw Stepkowski
,
O. Howard Frazier and
Heinrich Taegtmeyer*,,1
* Division of Cardiology and
Division of Organ Transplantation, University of Texas Houston-Medical School, Houston, Texas, USA; and
Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas, USA
1Correspondence: Department of Internal Medicine, Division of Cardiology, University of Texas Houston-Medical School, 6431 Fannin, MSB 1.222, Houston, TX 77030, USA. E-mail: heinrich.taegtmeyer{at}uth.tmc.edu
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ABSTRACT
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Mechanical unloading of the rat heart increases both protein synthesis and protein degradation. The transcriptional mechanism underlying increased protein synthesis during atrophic remodeling is not known. The aim of this study was to identify transcriptional regulators and the gene expression profile regulating protein synthesis in the unloaded rat heart and in the unloaded failing human heart. We measured DNA binding activity, transcript levels, and protein expression of transcriptional regulators of protein synthesis in a model of atrophic remodeling induced by heterotopic transplantation of the rat heart (duration 1 and 7 days). Using microarray analysis and quantitative RT-polymerase chain reaction, we found an increase in c-myc-regulated gene expression including an induction of ribosomal subunit messenger RNA’s (RPS 10, RPL 21) and rRNA (18S). Consistent with the gene expression profile, DNA binding activity of c-myc and the nuclear protein concentration of its coactivator, upstream binding factor (UBF), increased in the atrophied heart whereas protein levels of the c-myc inhibitor MAD1 decreased. We found the same increase of ribosomal subunit messenger RNA and rRNA in 21 paired samples of failing human hearts obtained before and after left ventricular assist device treatment (mean duration: 157±31 days). In summary, mechanical unloading increases c-myc activity and c-myc-regulated gene expression in the rat heart. Changes in transcript levels of genes regulating ribosomal biogenesis in the unloaded rat heart resemble those found in the unloaded failing human heart. We concluded c-myc and c-myc-regulated gene expression are transcriptional regulators of protein synthesis during atrophic remodeling of the heart.—Razeghi, P., Buksinska-Lisik, M., Palanichamy, N., Stepkowski, S., Frazier, O. H., Taegtmeyer, H. Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart.
Key Words: failing human heart • LVAD • reverse remodeling • c-myc
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INTRODUCTION
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ATROPHIC REMODELING OF the heart increases markers of both protein synthesis and protein degradation (1)
. The unexpected increase of protein synthesis during unloading-induced cardiac atrophy may be a compensatory response to counterbalance excessive atrophy or part of a rebuilding process that leads to a new equilibrium in protein turnover (2)
. We previously showed that p70S6K and 4EBP1, two downstream components of mTOR, are activated in the unloaded rat heart, suggesting that mTOR is one of the regulators of increased protein synthesis during atrophic remodeling (1)
. However, the transcriptional mechanism regulating protein synthesis during atrophic remodeling is not known.
The proto-oncogene c-myc promotes cell growth and protein synthesis (3)
. Inducible activation of c-myc increases transcript levels of ribosomal subunits, protein synthesis, and cell size in the heart (4)
. One mechanism by which c-myc increases protein synthesis is the transcriptional regulation of ribosomal biogenesis. MYC regulates the expression of numerous ribosomal subunit proteins and the expression of upstream binding factor (UBF), an HMG-box protein whose expression facilitates rDNA transcription (3)
. An important regulator of c-myc is the transcriptional repressor MAD1, which inhibits c-myc activity (3)
.
In the present study we investigated the transcriptional profile of the normal rat heart and the failing human heart subjected to mechanical unloading. Using microarray analysis we found that numerous transcripts of ribosomal subunits were increased. In addition, there was an increase in rRNA expression. Consistent with this gene expression profile, c-myc activity and nuclear protein levels of UBF increased in the unloaded heart whereas the c-myc inhibitor MAD1 decreased. We confirmed the increase of ribosomal subunit messenger RNA and rRNA in the unloaded failing human heart, suggesting that c-myc and c-myc-regulated gene expression are involved in the transcriptional regulation of protein synthesis during atrophic remodeling of the normal and the failing mammalian heart.
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MATERIALS AND METHODS
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Mechanical unloading of the normal rat heart
Male Wistar rats (160 to 200 g) underwent heterotopic heart transplantation as described previously (5)
. Briefly, isogenic infrarenal heterotopic heart transplantation was performed by anastomizing end-to-side the ascending aorta of the donor to the abdominal aorta of the recipient and the donor pulmonary artery to the recipient inferior vena cava. The use of animals and the animal protocol were approved by the Animal Welfare Committee of the University of Texas Houston Health Science Center.
On the first and seventh postoperative day, animals were anesthetized (pentobarbital, 100 mg/kg body wt intraperitoneally) and donor and recipient hearts were rapidly removed, freeze-clamped, and stored at –80°C for RNA and protein extraction at a later date.
Mechanical unloading of the failing human heart
We also studied 21 patients with end-stage heart failure, who underwent implantation of a left ventricular assist device at the Texas Heart Institute. The mean age was 52 ± 2 years, and 17 of the 21 patients were male. Causes of heart failure included idiopathic dilated cardiomyopathy (n=12), ischemic heart disease (n=8), and anthracycline-induced cardiomyopathy (n=1). The type of devices used included the Jarvik 2000 (n=11) and the Heartmate XVE (n=10). Paired left ventricular tissue (apex) was obtained at the time of implantation and explantation of the device. Mean duration on support was 157 ± 31 days. Tissue was immediately frozen in liquid nitrogen and stored at –80°C for RNA extraction at a later date.
Microarray analysis
Samples for microarray analysis were obtained from control and transplanted hearts of three experiments at 1 and 7 days after transplantation. The quality and quantity of the RNA samples were evaluated on an Agilent 2100 Bioanalyzer. The RNA (10–20 µg) was then converted into cDNA. The reverse transcriptase reaction was carried out with 50 µM dATP/dCTP/dGTP and a 50 µM mix of dTTP and aadUTP, 15 U of RNase Inhibitor, and 400 U MMLV reverse transcriptase at 42°C for 1 h. The template RNA was alkaline hydrolyzed, neutralized, and the cDNA pelleted. The cDNA was subsequently labeled with Amersham CyDye Post Labeling Dyes. The labeling reaction was then terminated with 4M hydroxylamine and cleaned through a spin column.
Hybridization was carried out overnight in a hybridization oven using Agilent hybridization chambers at 65°C with rotation. The arrays were washed according to the Agilent protocol for oligo arrays [Wash 1–6X saline-sodium citrate (SSC), 0.005% Triton X-102: Wash 2–0.1X SSC, 0.005% Triton X-102 chilled] and dried in a centrigfuge. The slides were scanned at 532 nM and 635 nM laser with an Axon 4200B at a pixel resolution of 10 µm with 2 line averaging. The tif images were saved into Genepix (version 5.2) and analyzed with criteria set up in the University of Texas-HSC-Houston Microarray Core Lab. Further analysis was provided using scripts developed in the core lab. Multiple chip experiments were analyzed using the program Acuity from Axon Technologies (Scottsdale, AZ, USA).
Gene expression
RNA was extracted by standard methods and analyzed by reverse transcription, followed by real-time quantitative polymerase chain reaction for the transcripts of interest by described methods (5)
. Transcript levels were normalized to total RNA measured in a spectrophotometer. Nucleotide sequences for probes as well as forward and reverse primers were published or are shown in Table 1
(6)
.
Protein expression
Nuclear proteins were extracted as recommended by active motive (cat. no. 40010). Protein concentrations were measured by the Bradford method (Sigma B-6916). Proteins were fractionated by 6% PAGE and transferred to a nitrocellulose membrane. Primary antibodies against UBF and MAD1 were purchased from Santa Cruz Biotechnology (sc-9131, Santa Cruz, CA, USA) and Novus Biologicals (NB 500–136, Littleton, CO, USA), respectively. Protein bands were quantified by densitometry using the Scion (version 1.63) software. Total UBF and MAD1 protein levels are shown in arbitrary units.
c-myc binding activity
Nuclear proteins were extracted as described above. The c-myc binding activity was measured using the TransAM c-myc Kit (Active Motif cat. no. 43396). This kit contains a 96-well plate, which has an immobilized oligonucleotide sequence that contains the c-myc consensus binding site (5'-CACGTG-3'). The active form of c-myc contained in nuclear extract binds specifically to this oligonucleotide. The primary antibody (Ab) used in the TransAM c-myc Kit recognizes an accessible epitope on c-myc protein on DNA binding. Addition of a secondary HRP-conjugated Ab provides a sensitive colorimetric readout, which is quantified by spectrophotometry.
Statistical analysis
Data are expressed as mean ± SE. Statistically significant differences between the two groups were determined using the Student’s t test. A value of P < 0.05 was considered as significant.
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RESULTS
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Mechanical unloading of the rat heart increases transcriptional markers of ribosomal biogenesis
Microarray analysis for transcriptional regulators of protein synthesis in the unloaded rat heart 1 and 7 days after heterotopic transplantation is shown in Table 2
. Nine genes increased and 3 genes decreased at least 1-fold in all three experiments at day 1 of unloading whereas 92 genes increased, and 19 genes decreased at least 1-fold in all three experiments at day 7 of unloading. Of those genes, which changed at least 1-fold in all three experiments we summarized the ones known to be involved in the regulation of protein synthesis in Table 2
. None of the genes that consistently decreased are known regulators of protein synthesis.
Because most of the genes in Table 2
encode for ribosomal subunit mRNAs, we decided to test the hypothesis that regulators and markers of ribosomal biogenesis are activated during atrophic remodeling of the unloaded rat heart. Consistent with the microarray data, we validated the increase of transcript levels of a small and a large ribosomal subunit (RPS 10 and RPL 21) in hearts that were unloaded for 7 days using quantitative RT-polymerase chain reaction (Fig. 1
). There was no significant change in gene expression of RPS 10 and RPL 21 at day 1 of unloading (data not shown). Because ribosomal biogenesis is dependent on the increased transcription of ribosomal DNA, we also measured gene expression of the rRNA 18S. Similar to the changes of the ribosomal subunit mRNA, transcript levels of 18S rRNA also increased at 7 days of unloading (Fig. 1)
but not 1 day after transplantation (data not shown).
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Figure 1. Transcript levels of ribosomal subunits (RPS 10 and RPL 21) and of a rRNA (18S) significantly increase after 7 days of unloading in the rat heart, *P < 0.05, **P < 0.01, n = 5.
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Mechanical unloading of the rat heart increases c-myc activity
Because ribosomal biogenesis is transcriptionally regulated by the transcription factor c-myc, we measured c-myc activity, protein levels of the c-myc coactivator (UBF), and protein levels of the c-myc repressor (MAD1) in the unloaded rat heart. Figure 2
shows that c-myc activity significantly increased after 1 day of unloading. In contrast, at day 7 of unloading c-myc activity was not significantly changed (data not shown). However, consistent with the increase in c-myc activation, we found increased nuclear protein levels of UBF 7 days after transplantation (Fig. 2)
. In contrast, protein levels of the c-myc repressor MAD1 decreased in the unloaded heart 1 and 7 days after transplantation (Fig. 2)
.
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Figure 2. Mechanical unloading of the rat heart significantly increases c-myc activation and decreases MAD1 protein levels, *P < 0.05, n = 6. Nuclear protein levels of UBF significantly increase after 7 days of unloading of the rat heart, *P < 0.05, n = 5. c, control; u, unloading.
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Mechanical unloading of the failing human heart increases ribosomal subunit messenger RNA and rRNA
To test whether the findings of the unloaded normal rat heart also play a role in the unloaded failing human heart, we measured transcript levels of the ribosomal subunit RPS 10 and the rRNA 18S in paired myocardial samples of failing human heart before and after mechanical unloading with a LVAD. Consistent with our findings in the unloaded rat heart, RPS 10 and 18S transcript levels significantly increased in the unloaded failing human heart (Fig. 3
). The small sample size precluded an analysis of protein expression of regulators and markers of ribosomal biogenesis in the human tissue.
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Figure 3. Mechanical unloading of the failing human heart significantly increases transcript levels of RPS 10 and 18S, *P < 0.05, n = 21.
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DISCUSSION
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The main findings of the study are that unloading of the normal rat heart increases c-myc activity and c-myc-regulated gene expression, both of which are essential for ribosomal biogenesis. Consistent with the findings in the unloaded rat heart, transcriptional markers of ribosomal biogenesis increase in the unloaded failing human heart as well.
Atrophic remodeling increases markers of protein synthesis
Mechanical unloading of the rat heart increases the phosphorylation of p70S6K and 4EBP1, two downstream effectors of mTOR (1)
. Phosphorylation of both proteins can be prevented by the mTOR inhibitor rapamycin, indicating that mTOR activation is involved in the up-regulation of protein synthesis during atrophic remodeling of the heart. Although an increase of protein synthesis during atrophy seems counterintuitive, the process may serve as a mechanism to prevent an excessive decrease in heart size. Indeed, blocking mTOR activity during cardiac atrophy augments the decrease in cardiac size (1)
. In addition to the phosphorylation of p70S6K and 4EBP1, mTOR regulates ribosomal gene transcription by activating the transcription factor UBF (7)
. The parallel increase in UBF protein levels and rRNA has been described in myotubes exposed to hypertrophic stimuli (8)
. Consistent with our previous observation of increased mTOR activation in the atrophied heart, we now find increased nuclear protein levels of UBF and an increase in a transcript concentration of a rRNA. rRNA makes up the majority of total RNA. One possible explanation for the increase in the rRNA (18S) with no change in total RNA (data are normalized to total RNA) is that during ribosomal biogenesis maturation of prerRNA increases. Therefore, the increase in 18S rRNA (a form of mature rRNA) suggests that rRNA processing is increased during unloading whereas the combined amount of mature RNA and prerRNA may not change. This is consistent with our finding of increased c-myc activity in the unloaded heart, because c-myc is a known activator of rRNA maturation (9)
. Thus, our new findings suggest that atrophic remodeling in the heart increases protein synthesis by transcriptional and post-transcriptional mechanisms (Fig. 4
).
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Figure 4. Atrophic remodeling increases protein synthesis by activating mTOR and up-regulating transcriptional markers of ribosomal biogenesis.
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The proto-oncogene c-myc regulates the transcriptional control of ribosomal biogenesis
Myc activates several genes that encode ribosomal proteins (10)
, rRNA genes (11)
, translation factors (12)
, and proteins involved in the biogenesis and processing of rRNAs by binding directly to their promoters (13)
. The activity of c-myc is regulated by coactivators and corepressors (3)
. Studies in granulocytes have shown that during ribosomal biogenesis, rRNA production positively correlates with c-myc activity and UBF levels and negatively correlates with levels of the c-myc inhibitor MAD1 (14)
. Inducible activation of c-myc increases protein synthesis and cell size during hypertrophic remodeling of the heart (4)
. In contrast, the role of c-myc in atrophic remodeling is not known. We show that increased expression of ribosomal subunit mRNA and rRNA correlates positively with increased c-myc activity and with increased UBF levels, and correlates negatively with MAD1 protein expression. We also found that the activation of c-myc was earlier than the increase of UBF protein levels in the nucleus and earlier than the increase in transcript levels of ribosomal subunit mRNA and rRNA. One possible explanation for this sequential activation of transcription factors is the transcriptional regulation of UBF by c-myc (14)
. This finding is consistent with studies showing that an increase in UBF levels is necessary for the induction of ribosomal genes (15)
. Together, these findings suggest that increased protein synthesis in the atrophied rat heart is at least partially regulated by c-myc, c-myc-regulated genes, and UBF (Fig. 4)
.
Mechanical unloading of the failing human heart increases transcriptional markers of ribosomal biogenesis
Mechanical unloading of the failing human heart increases transcript levels of a ribosomal subunit mRNA and a rRNA, replicating the findings of the unloaded normal rat heart. Structural markers of myocyte damage decrease after mechanical unloading of the failing human heart (16
, 17)
. The increase in markers of ribosomal biogenesis may be one way the failing cardiomyocyte "rebuilds" itself during unloading. One possible activator of protein synthesis during atrophic remodeling is insulin-like growth factor (IGF)-1. We and others have shown that myocardial IGF-1 transcript levels increase both in the normal unloaded rat heart and in the unloaded failing human heart (18
,19)
. IGF-1 increases c-myc expression through a phospholipase 3 beta-dependent pathway in cardiomyoctes (20)
. Therefore, we propose that IGF-1 is one of the upstream signals activating c-myc-regulated gene expression during atrophic remodeling.
Study limitations
In the present study we found that unloading of the normal rat heart for up to 7 days and unloading of the failing human heart for 157 ± 31 days induce similar inductions of transcriptional markers of ribosomal biogenesis. The heterotopically transplanted rat heart does not exactly mimic the unloaded failing human heart, because 1) it is not diseased heart and 2) the duration of unloading differs. Despite these differences unloading induced similar changes in transcriptional markers of ribosomal biogenesis, suggesting that this effect is independent of the baseline condition of the unloaded heart and that the transcriptional changes are induced in the early and sustained in the later course of unloading. Neither model allows us to determine whether the changes in markers of ribosomal biogenesis are specific for cardiomyocytes or for other cell types in the myocardium. The lack of a model that mimics unloading in isolated cardiomyocytes or an assay that measures specifically cardiomyocyte c-myc activity in vivo precludes such an analysis.
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CONCLUSIONS
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Atrophic remodeling of the heart increases c-myc activity, UBF protein levels, and transcriptional markers of ribosomal biogenesis, suggesting a transcriptional mechanism increasing protein synthesis in the unloaded heart. This mechanism may contribute to the repair and regeneration of sarcomeric damage during reverse remodeling in the unloaded failing human heart.
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ACKNOWLEDGMENTS
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Work in our laboratory is supported in part by a grant from the NHLBI (RO1-HL/AG 61483) of the US Public Health Service. P.R. is the recipient of a fellowship from the Roderick Duncan MacDonald General Research Fund of St. Luke’s Episcopal Hospital, Houston, TX, USA. We thank Xiumei Qu and Rebecca L. Salazar for expert technical assistance.
Received for publication January 9, 2006.
Accepted for publication February 12, 2006.
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ABSTRACT
INTRODUCTION
