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Cardiovascular Research 2007 74(1):133-139; doi:10.1016/j.cardiores.2006.12.021
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Copyright © 2007, European Society of Cardiology

Lack of NF-{kappa}B1 (p105/p50) attenuates unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression in rodent heart

Peter Razeghia, Mou-Er Wangb, Keith A. Youkerc, Leonard Golfmand, Stanislaw Stepkowskib and Heinrich Taegtmeyera,*

aDivision of Cardiology, University of Texas Houston-Medical School, Houston, Texas, USA
bDivision of Organ Transplantation, University of Texas Houston-Medical School, Houston, Texas, USA
cDepartment of Surgery, Baylor College of Medicine, Houston, Texas, USA
dDepartment of Cardiothoracic and Vascular Surgery, University of Texas Houston-Medical School, Houston, Texas, USA

* Corresponding author. Department of Internal Medicine, Division of Cardiology, University of Texas Houston-Medical School, 6431 Fannin, MSB 1.222, Houston, TX 77030, USA. Tel.: +1 713 500 6569; fax: +1 713 500 0637. Email address: heinrich.taegtmeyer{at}uth.tmc.edu

Received 24 July 2006; revised 19 December 2006; accepted 22 December 2006


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and PPAR{alpha}-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-{kappa}B regulates the fetal gene program and PPAR{alpha}-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-{kappa}B is the regulator for activation of the fetal gene program, for downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading.

Methods: Activation of the inhibitory {kappa} B kinase β (IKKβ)/NF-{kappa}B pathways were measured in the heterotopically transplanted rat heart using Western blotting of total and phospho-IKKβ and using transcription factor ELISA's for the five members of the NF-{kappa}B family (p65 (Rel A), p105/p50, c-Rel, RelB, and p100/p52). In loss of function experiments, we transplanted hearts of p105/p50 knockout mice into wildtype mice and compared changes in gene expression and cardiomyocyte size with wildtype hearts transplanted into wildtype mice.

Results: Total and phospho-IKKβ levels significantly increased in the transplanted heart seven days after surgery. The activation of IKKβ was paralleled by increased DNA binding activity of p65 and p105/p50. Mechanical unloading induced myosin heavy chain β expression and decreased cardiomyocyte size in hearts of both wildtype and p105/p050 knockout animals. In contrast, the downregulation of PPAR{alpha} and MCAD was significantly attenuated or prevented in the hearts of p105/p50 knockout mice.

Conclusions: The IKKβ/p65/p50 pathway is activated in the unloaded rodent heart and a likely regulator for the downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression.

KEYWORDS Atrophy; Remodeling; PPAR alpha; NF-{kappa}B; Unloading


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Atrophic remodeling of the unloaded rat heart reactivates the fetal gene program (e.g. increase in myosin heavy chain beta (MHCβ)), decreases peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and PPAR{alpha}-regulated gene expression and decreases cardiomyocyte size [1–3]. The molecular mechanisms regulating the transcriptional and trophic response of the unloaded heart are unknown. One possible regulator is NF-{kappa}B. This transcription factor consists of five family members (p65, p105/p50, c-Rel, RelB, and p52) [4]. Out of these five family members only p105/p50 is essential for skeletal muscle atrophy, as well as for the activation of the fetal gene program and downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression during cardiac hypertrophy [5–8].

p105/p50 plays a central role during skeletal muscle atrophy, because it is involved in both the formation of p65/p50 heterodimers (disuse atrophy) and the formation of p50/p50 homodimers (cachexia atrophy) [9]. p50 is generated from the partial processing of its cytoplasmic precursor p105. The formation and nuclear translocation of hetero- or homodimers of the NF-{kappa}B family members is regulated by Inhibitory {kappa} B kinase (IKK) [4]. In the present study we tested the hypothesis that the IKK/NF-{kappa}B pathway is activated and essential for unloading-induced upregulation of MHCβ, unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression, and cardiomyocyte atrophy. We used the heterotopically transplanted rodent heart as a model to study cardiac unloading. Seven days of unloading significantly increased protein levels of total and phospho-IKKβ, DNA binding activity of p65 and p105/p50, and transcript levels of MHCβ. PPAR{alpha} and PPAR{alpha}-regulated gene expression and cardiomyocyte size significantly decreased in the same model. In a loss of function experiment, we transplanted hearts of p105/p50–/– knockout mice into wildtype mice and compared the transcriptional and trophic response with wildtype hearts transplanted into wildtype mice. Both the upregulation of MHCβ and the decrease in cardiomyocyte size did not significantly differ between unloaded p105/p50–/– hearts and unloaded wildtype hearts. In contrast, unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression was significantly attenuated or prevented in unloaded hearts of p105/p50–/– mice, suggesting that p105/p50 is involved in unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1 Mechanical unloading of the rodent heart
Heterotopic heart transplantation was performed in male Wistar rats (160 to 200 g, n=7) or in B6;129 mice (n=5) as previously described [3,10]. For the loss of function experiments we transplanted hearts of 6-week-old male B6;129 or p105/p50–/– deficient B6;129 mice into 6-week-old male B6;129 mice. We did not detect any p105/p50 in hearts of p105/p50–/– deficient B6;129 mice, consistent with previous studies (data not shown) [8]. 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 perioperative mortality was 0% and 9% for rats and mice, respectively. Experiments were terminated 7 days after surgery. We chose this time point, because the greatest reduction of atrophy is measured within this time period without any evidence of fibrosis or inflammation [3]. There was no significant difference between the heart weight to body weight ratio between both mouse strains at baseline (5.01±0.08 vs. 5.30±0.21, n=5, ns). All mice were obtained from the Jackson laboratory (Bar Harbor, Maine, USA). Previous studies have shown that activation of NF-{kappa}B is completely abolished in hearts of p105/p50–/– mice [6]. The use of animals and the animal protocol were approved by the Animal Welfare Committee of the University of Texas Houston Health Science Center, and conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

On the seventh postoperative day, animals were anesthetized (pentobarbital, 100 mg/kg body weight 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. The native heart was used as a control for the unloaded heart. In addition, we harvested hearts from and p105/p50–/– mice without surgery in order to measure baseline gene expression levels and cardiomyocyte size. Tissue for histological analysis was stored in paraformaldehyde (2%).

2.2 Protein expression
Nuclear proteins were extracted as recommended by active motive, Carlsbad, CA, USA (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 total and phospho-IKKβ were purchased from Cell Signaling, Danvers, MA, USA and the antibody against beta-tubulin was purchased from Santa Cruz Biotechnology, Santa Cruz, CA, USA. Protein bands were quantified by densitometry using the Scion (version 1.63) software. Total and phospho-IKKβ protein levels are shown in arbitrary units.

2.3 DNA binding activity
DNA binding activity of all five NF-{kappa}B family members was measured using the Trans-AM assays from active motive, Carlsbad, CA, USA (cat. no. 43296). This kit contains a 96-well plate, which has an immobilized oligonucleotide sequence, that contains the NF-{kappa}B consensus binding site. The active forms of the NF-{kappa}B family members contained in nuclear extract bind specifically to this oligonucleotide. The primary antibodies used in the TransAM NF-{kappa}B Kit recognize an accessible epitope on the NF-{kappa}B proteins upon DNA binding. Addition of a secondary HRP-conjugated antibody provides a sensitive colorimetric readout, which is quantified by spectrophotometry.

2.4 Gene expression
RNA was extracted by standard methods and analyzed by reverse transcription followed by real-time quantitative PCR for the transcripts of interest by methods described previously [1]. Transcript levels were normalized to cyclophilin A. Cyclophilin A levels did not significantly differ between the groups (data not shown). Nucleotide sequences for probes as well as forward and reverse primers were previously published [11,12].

2.5 Cardiomyocyte size determination
Hematoxylin–eosin staining was used to measure myocyte size. A point-to-point perpendicular line was drawn across the cross-sectional area of the myocytes at the level of the nucleus and the diameter length was measured using Image-Pro Plus from MediaCybernetics, Silver Spring, MD, USA. Transverse- or oblique-sectioned myocytes were excluded. Fifty myocytes per slide were measured from each tissue specimen.

2.6 Statistical analysis
Data are expressed as mean±SEM. Differences between the groups were calculated by a 1-way ANOVA followed by a Bonferroni test. A value of P<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1 Mechanical unloading of the rat heart activates the IKKβ/p65/p105/p50 pathway
Fig. 1 shows total and phospho-IKKβ protein levels in the normal and unloaded rat heart. Both total and phospho-IKKβ protein levels significantly increased in the unloaded heart. Beta-tubulin, used as a loading control, did not significantly differ between the two groups. The increase in total and phospho-IKKβ protein levels were paralleled by increased DNA binding activity of the NF-{kappa}B family members p65 and p105/p50, but not c-Rel, RelB, or p52 in the unloaded rat heart seven days after surgery (Fig. 2).


Figure 1
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  		Fig. 1 Seven days of mechanical unloading significantly increase protein levels of total and phospho-IKKβ levels in the rat heart (n=7, *p<0.05). Fig. 1a shows representative western blots and Fig. 1b shows densitometry of total and phospho-IKKβ protein expression normalized to beta-tubulin in the control and unloaded heart.

 

Figure 2
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  		Fig. 2 DNA binding activities of p65 (a) and p50 (b), but not c-Rel (c), Rel-B (d), or p52 (e) significantly increase in the unloaded rat heart seven days after surgery (n=7, *p<0.05).

 
3.2 Mechanical unloading increases MHCβ gene expression in hearts of and p105/p50–/– knockout mice
Transcript levels of MHCβ significantly increased in unloaded hearts of wildtype and p105/p50–/– mice (Fig. 3a). There was no significant difference of MHCβ transcript levels between the two groups of unloaded hearts. Baseline gene expression of MHCβ did not significantly differ between hearts from wildtype and p105/p50–/– mice (data not shown).


Figure 3
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  		Fig. 3 Mechanical unloading of the mouse heart significantly increases MHCβ, and decreases PPAR{alpha} in hearts of wildtype and p50–/– mice (a, b, n=5, *p<0.05, **p<0.01, ***p<0.001). MCAD gene expression only significantly decreased in unloaded wildtype hearts (n=5, **p<0.01), but only showed a trend to decrease in unloaded p50–/– hearts (c, p=0.10). Transcript levels of PPAR{alpha} and MCAD were significantly higher in unloaded hearts of p50–/– mice than in unloaded hearts of mice (b, c, n=5, #p<0.05, ##p<0.01). PDK4 and UCP3 gene expression significantly decreased in unloaded hearts and increased in unloaded p50–/– hearts (d, e, n=5, *p<0.05, **p<0.01). Transcript levels of PDK4 and UCP3 were significantly higher in unloaded hearts of p50–/– mice than in unloaded hearts of mice (d, e, n=5, ##p<0.01, ###p<0.001).

 
3.3 Lack of p105/p50–/– attenuates unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression
Fig. 3b shows changes in transcript levels of PPAR{alpha} and the PPAR{alpha}-regulated genes (medium-chain acyl-CoA dehydrogenase (MCAD), uncoupling protein 3 (UCP3), and pyruvate dehydrogenase kinase 4 (PDK4)). Mechanical unloading significantly decreased transcript levels of PPAR{alpha} in hearts of wildtype and of p105/p50–/– mice. The downregulation of PPAR{alpha} transcript levels was significantly attenuated in hearts of p105/p50–/– mice. Consistent with the attenuated downregulation of PPAR{alpha} in unloaded hearts of p105/p50–/– mice, gene expression of MCAD only decreased significantly in unloaded hearts of wildtype mice, but not in unloaded hearts of p105/p50–/– mice. In addition, the expression of two other PPAR{alpha}-regulated genes (UCP3 and PDK4) did not decrease in unloaded hearts of p105/p50–/– mice, but instead significantly increased. There was no difference between PPAR{alpha} and PPAR{alpha}-regulated gene expression between the two control groups (native hearts, Fig. 3b) or between hearts of wildtype and p105/p50–/– mice at baseline (data not shown).

3.4 Mechanical unloading decreases cardiomyocyte size in hearts of and p105/p50–/– knockout mice
Fig. 4 shows the histology of native hearts and unloaded and p105/p50–/– hearts. The cardiomyocyte size of both unloaded and unloaded p105/p50–/– hearts, significantly decreased seven days after surgery when compared to the native hearts. Cardiomyocyte size of the wildtype and of the p105/p50–/– hearts did not differ at baseline (data not shown) or at seven days of unloading (Fig. 4).


Figure 4
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  		Fig. 4 Hematoxylin–eosin staining of native (a and c), unloaded wildtype hearts (b), and unloaded hearts of p50–/– mice (d). Cardiomyocyte size significantly decreased in unloaded wildtype and unloaded p50–/– hearts (e, n=5, **p<0.01) and did not significantly differ between the two groups.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
The main findings of the study are that in the unloaded rodent heart the IKKβ/p65/p105/p50 pathway is activated, and lack of p105/p50 significantly attenuates or prevents downregulation of PPAR{alpha} and the PPAR{alpha}-regulated gene expression.

4.1 The fetal gene program is activated during atrophic and hypertrophic remodeling
In the heart, both pressure-induced hypertrophy and unloading-induced atrophy reactivate the fetal gene program [1,13]. This activation includes an increase in the fetal isogene MHCβ. The molecular mechanisms regulating the activation of the fetal gene program in the unloaded heart are still unknown. Because in the hypertrophied heart, inhibition of NF-{kappa}B prevents the induction of fetal genes [5,6], we examined the hypothesis that NF-{kappa}B is essential for the induction of MHCβ in the unloaded heart. Genetic disruption of p105/p50 prevents NF-{kappa}B activation [6]. Mechanical unloading of hearts from p105/p50–/– mice does not prevent induction of MHCβ, suggesting that NF-{kappa}B is not essential for unloading-induced activation of MHCβ. In the unloaded heart other transcription factors (e.g. GATA4 and NF-AT3) appear to regulate MHCβ gene expression independent of NF-{kappa}B [14].

4.2 Lack of NF-{kappa}B1 (p105/p50) attenuates unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression
Another common transcriptional response of the hypertrophied and atrophied heart is the downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression [2,15]. The mechanism for the decrease of PPAR{alpha}-regulated genes in the hypertrophied heart is not fully understood. Activation of NF-{kappa}B during cardiac hypertrophy leads to downregulation of PPAR{alpha}-regulated gene expression (e.g. pyruvate dehydrogenase kinase 4) [7]. NF-{kappa}B binds to PPAR and may act as a co-repressor [7]. Another study has shown that angiotensin II-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression in cardiomyocytes can be prevented by inhibiting p50 [16]. Because NF-{kappa}B is activated in the unloaded heart, this mechanism may also contribute to the downregulation of PPAR{alpha}-regulated gene expression. Lack of p105/p50 prevents NF-{kappa}B activation and therefore may prevent the repressing effect of NF-{kappa}B on PPAR and prevent the downregulation of PPAR{alpha}-regulated gene expression. In the present study we found that PPAR{alpha} and PPAR{alpha}-regulated gene expression (MCAD, UCP3, and PDK4) do not significantly differ at baseline between hearts of wildtype and p105/p50–/– mice. In contrast, unloading-induced downregulation of PPAR{alpha} was attenuated in p105/p50–/– hearts, suggesting that the repressing effect of p105/p50 on PPAR{alpha} and PPAR{alpha}-regulated gene expression is dependent on unloading. The decrease in PPAR{alpha}-regulated gene expression in the unloaded heart is consistent with the decrease in fatty acid oxidation and the increase in glucose oxidation in the same model [17]. We have previously shown that activation of PPAR{alpha} in the hypertrophied heart impaired cardiac function, suggesting that the downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression may be essential for the maintenance of contractile function of the hypertrophied heart [15]. In contrast, the significance of the downregulation of PPAR{alpha}-regulated gene expression and fatty acid oxidation in the unloaded heart is not known. The downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression in different cardiac phenotypes (e.g. atrophy and hypertrophy) is correlative and does not imply PPAR{alpha} as an essential regulator for changes in cardiac mass. The attenuated downregulation of PPAR{alpha} (e.g. in the unloaded p105/p50–/– KO hearts) did not significantly attenuate atrophy in the unloaded heart, suggesting that PPAR{alpha} is not a regulator of cardiomyocyte atrophy.

4.3 The ubiquitin proteasome system is activated in the unloaded rat heart
The ubiquitin proteasome system (UPS) is the main regulator of protein degradation during muscle atrophy [18]. Like in skeletal muscle, the UPS is activated during atrophic remodeling of the unloaded heart [3,19]. Several signaling pathways regulate the UPS. The IKKβ/NF-{kappa}B pathway is activated and essential for skeletal muscle atrophy [8,20]. NF-{kappa}B transcription factors are homo- or heterodimers that translocate to the nucleus and bind DNA through a Rel-homology domain [4]. Five mammalian members of the NF-{kappa}B family have been identified: NF-{kappa}B1 (p105/p50 and its precursor p105), NF-{kappa}B2 (p52 and its precursor p100), c-Rel, RelA (p65), and RelB [4]. Two of the five family members (p105/p50 and p65) are involved in the regulation of skeletal muscle atrophy [9]. P105/p50 has a central role in muscle atrophy because it forms either homodimers during disuse atrophy or heterodimers (with p65) during cachexia-induced atrophy [9]. Mice lacking the p105/p50 gene are resistant to the decrease in soleus fiber cross-sectional area that results from 10 days of hindlimb unloading [8]. Consistent with the findings in skeletal muscle we also found an activation of the IKKβ/NF-{kappa}B pathway in the unloaded rat heart and increased DNA binding activity of p105/p50 and p65. In contrast to skeletal muscle, we did not find that lack of p105/p50 attenuates unloading-induced cardiomyocyte atrophy, suggesting that in the heart other signaling pathways are essential for the regulation of atrophy.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Unloading of the rodent heart activates the IKKβ/NF-{kappa}B pathway. Lack of p105/p50 does not affect the increase in MHCβ gene expression or the decrease in cardiomyocytes size, but attenuates or prevents unloading-induced downregulation of PPAR{alpha} and PPAR{alpha}-regulated gene expression. These findings suggest that NF-{kappa}B is a transcriptional regulator, which plays a role in the switch of energy substrate preference in the unloaded heart.


   Acknowledgements
 
Work in our laboratory was supported, in part, by a grant from the NHLBI (RO1-HL/AG 61483) of the US Public Health Service. Peter Razeghi was the recipient of a fellowship from the Roderick Duncan MacDonald General Research Fund of St. Luke's Episcopal Hospital, Houston, Texas.

We thank Mei Gong and Rebecca L. Salazar for technical assistance.


   Notes
 
Time for primary review 38 days


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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