Physiol. Genomics AJP: Heart and Circulatory Physiology
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Physiol. Genomics 30: 1-7, 2007. First published February 27, 2007; doi:10.1152/physiolgenomics.00246.2006 Free Article
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Received 9 November 2006; accepted in final form 20 February 2007.
Physiological Genomics 30:1-7 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

Gene profiling during regression of pressure overload-induced cardiac hypertrophy

Dong Kwon Yang 1, Bo Youn Choi 1, Young-Hoon Lee 2, Young-Gyu Kim 3, Myeong-Chan Cho 3, Seong-Eui Hong 1, Do Han Kim 1, Roger J. Hajjar 4 and Woo Jin Park 1

1 Department of Life Science, Gwangju Institute of Science and Technology, Gwangju
2 Department of Oral Anatomy, Chonbuk National University, Jeonju
3 Department of Internal Medicine, Chungbuk National University, Cheongju, Korea
4 Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Regression of cardiac hypertrophy and improvement of the functional capacity of failing hearts have reportedly been achieved by mechanical unloading in cardiac work. In this study, cardiac hypertrophy was first induced in rats by transverse aortic constriction and then mechanically unloaded by relieving the constriction after significant cardiac hypertrophy had developed. Hypertrophy was significantly regressed at the cellular and molecular levels at day 1, 3, and 7 after constriction relief. Gene profiling analysis revealed that 52 genes out of 9,911 genes probed on a gene array were specifically upregulated during the early regression period. Among these regression-induced genes, Eyes absent 2 (eya2) was of particular interest because it is a transcriptional cofactor involved in mammalian organogenesis as well as Drosophila eye development. Adenovirus-mediated overexpression of eya2 in rat neonatal cardiomyocytes completely abrogated phenylephrine-induced development of cardiomyocyte hypertrophy as determined by cell size, sarcomere rearrangement and fetal gene re-expression. Our data strongly suggest that transcriptional programs distinct from those mediating cardiac hypertrophy may be operating during the regression of hypertrophy, and eya2 may be a key regulator of one of these programs.

remodeling; eya2


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
CARDIAC HYPERTROPHY IS a cellular process marked by the enlargement of cardiac myocytes, accumulation of sarcomeric proteins, and reorganization of the myofibrillar structure. Although cardiac hypertrophy, in its initial stages, is regarded as a compensatory response to increased mechanical load, the hypertrophic heart often progresses to a pathological state (12). As a result, cardiac hypertrophy is an independent and major risk factor for cardiovascular morbidity and mortality. The cellular and molecular events associated with cardiac hypertrophy have been intensively characterized during the last decade (for review articles see Refs. 10, 16, 22).

Interest in mechanical unloading and/or regression of cardiac hypertrophy has been intensified in part because the left ventricular assist system (LVAD) has become more common in clinical use. Clinical trials have shown that unloading terminally failing hearts by LVAD reversed hypertrophy and improved cardiac contractility, thereby eliminating the need for transplantation (5, 17, 21, 28). In other clinical studies of patients with aortic stenosis, regression of cardiac hypertrophy was observed after aortic valve replacement (3, 13, 25). However, few data are available on the molecular mechanism underlying the regression of cardiac hypertrophy.

An intriguing question is whether regression of cardiac hypertrophy is merely a reversal of cardiac hypertrophy or a separate process coupled with unique signaling pathways. If the latter were the case, augmenting these regression-associated pathways would provide a novel approach for treatment of cardiac hypertrophy and heart failure. In this study, we utilized a surgical model for regression of cardiac hypertrophy. Using DNA microarray analysis, we were able to identify a set of genes specifically induced during the regression period and observed that one of these regression-induced genes, Eyes absent 2 homolog (eya2), blocks the development of cardiomyocyte hypertrophy in neonatal cardiomyocytes.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Surgical procedures.
All animal experiments in this study were performed with the approval of the Animal Care Committee of Gwangju Institute of Science and Technology. Pressure overload-induced hypertrophy in the rat heart was performed as described previously (4, 20). Briefly, 200- to 230-g Sprague-Dawley rats were anesthetized by intraperitoneal injection of a mixture of ketamine (120 mg/kg) and xylazine (10 mg/kg). Left-sided thracotomies were conducted to expose the transverse aorta, while the rats were constantly ventilated (Harvard Apparatus). The transverse aorta was then banded (4-0 silk) with an overlaying blunted 22-gauge needle, and then the needle was quickly removed to create a defined constriction. Sham operations were also performed in which the transverse aorta was exposed but not banded. To unload the hypertrophied hearts, the constriction was relieved by untying the silk ligature 2 wk after the initial banding surgery. Before and after relieving the constriction, we monitored the pressure in the right carotid artery to confirm the restoration of normal aortic blood flow.

Histological analysis of hearts.
Rats were killed and hearts were arrested at end-diastole, and the left ventricle was freed from the right ventricle and weighed. Paraffin-embedded hearts were cut into 5-µm slices and stained with a hematoxylin-eosin solution. Sections were observed under an Axiophot microscope (Carl Zeiss) and analyzed with AnalysisSIS3.2 software (Soft-Imaging System).

cDNA microarray.
Total RNA was prepared from four left ventricles for each experiment and subjected to hybridization to the CodeLink Uniset Rat I Expression Bioarray (Amersham), which contains 9,911 transcripts according to the manufacturer's recommendations by Digital Genomics (Seoul, Korea). The processed slides were scanned with a GenePix 4000B Scanner (Molecular Devices) and analyzed with the CodeLink Expression Analysis Software (Amersham). Reproducibility of the obtained data was assessed by scatter-plot analysis of normalized probe signals. The data set with the lowest correlation coefficient among the four data sets at each point was discarded, and the remaining three data sets were subjected to further analysis.

Quantitative real-time PCR.
Total RNA was isolated with TRI reagent (Sigma). Reverse-transcriptase reactions were performed using ImProm II reverse-transcriptase (Promega) with oligo-dT priming. Quantitative real-time PCR (qRT-PCR) was performed using an ABI PRISM Sequence Detection System 7500 (Applied Biosystems) with SYBR Green (Takara) as fluorescent and ROX (Takara) as reference dyes.

Cell culture and hypertrophic stimulation.
Primary cultures of cardiomyocytes from 2-day-old Sprague-Dawley rats were prepared as described (11). In brief, ventricular tissue was enzymatically dissociated, and the resulting cell suspension was enriched for cardiomyocytes using Percoll (Amersham) step gradients. Cells were plated onto either collagen-coated culture dishes or coverslips and cultured in cardiomyocyte culture medium (DMEM supplemented with 10% fetal bovine serum and 2 mM L-glutamine, GIBCO-BRL). To induce hypertrophy, cardiomyocytes were cultured in serum-free medium for at least 24 h and then treated with 100 µM PE for 24 h.

Generation of recombinant adenovirus AdEya2.
The AdEasy-1 Expression System Kit (Stratagene) was used to generate recombinant adenoviruses. Full-length mouse eya2 cDNA tagged with HA at its amino terminus was subcloned into the pAdTrack-CMV vector. The entire expression cassette from the vector was excised and inserted into the subcloning site of the AdEasy-1 viral vector. This recombinant adenoviral plasmid was transfected into HEK293 cells to generate the infectious viral particles, AdEya2. Cardiomyocytes were infected with recombinant adenoviruses for 2 h at a multiplicity of infection of 50–100 particles/cell and incubated for an additional 24–48 h to ensure transgene expression.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Regression of cardiac hypertrophy.
The transverse aortic constriction (TAC), applied for 2 wk, caused prominent cardiac hypertrophy; the left ventricle wt/body wt ratio in rats with aortic constriction was 30.3% greater than the ratio in sham-operated rats (P < 0.05, Fig. 1A). The constriction was relieved after 2 wk by surgically removing the silk ligature, and the hearts were examined at day 1, 3, and 7 after the constriction removal, denoted as TAC-R1, TAC-R3, and TAC-R7, respectively. At TAC-R1, the cardiac hypertrophy was significantly regressed as measured by the left ventricle wt/body wt ratio (12.7% increase compared with sham hearts, P < 0.05; Fig. 1A). At TAC-R3 and TAC-R7, cardiac hypertrophy appeared to have completely regressed. Serial histological sections of hearts also demonstrated a progressive regression of cardiac hypertrophy after removal of the constriction (Fig. 1B). Examination of the sections at higher magnification revealed that the development and the regression of cardiac hypertrophy were associated with cardiomyocyte enlargement and normalization, respectively (Fig. 1B). Development of cardiac hypertrophy and regression of the established cardiac hypertrophy were further confirmed by Northern blot analysis of atrial natriuretic factor (ANF) expression (Fig. 1C). These data indicate that our surgical model resulted in the regression of cardiac hypertrophy at the cellular and molecular levels.


Figure 1
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  		Fig. 1. Pressure overload-induced cardiac hypertrophy and regression of the established cardiac hypertrophy. A: left ventricle weight/body wt (LVW/BW) (mean ± SD, Sham, n = 3; TAC14, n = 9; TAC-R1, n = 7; TAC-R3, n = 3; TAC-R7, n = 3). *P < 0.05 vs. sham group. B: hematoxylin-eosin staining of the representative sections. The surface areas of individual cardiomyocytes were measured using the AnalySIS image analysis software. Scale bar, 2 mm (top), 20 µm (bottom). C: expression of atrial natriuretic factor (ANF) (GAPDH as a control) in the left ventricles at each point was analyzed by Northern blotting. TAC, transverse aortic constriction.

 
Expression profiling.
For expression profiling analysis, we chose four time points: Sham-operated (Sham), 1 day after TAC (TAC1), 14 days after TAC (TAC14), and 14 days after TAC with 1 day of constriction relief (TAC-R1). Average values of the expression levels in the experimental hearts relative to the sham-operated hearts were clustered and illustrated graphically (Fig. 2). Visual scanning of the data revealed a number of temporal expression patterns. In some clusters (group I), the gene expression increased at TAC14 and decreased sharply at TAC-R1. In a second group of clusters (group II), the genes that were upregulated at TAC14 remained elevated at TAC-R1. We suggest that genes in group I participate in hypertrophic signaling pathways, and genes in group II participate in counteracting the hypertrophic signaling. However, this speculation remains to be tested. Genes in the third clusters (group III) are induced only at TAC-R1. We suggest that these genes might be involved antihypertrophic or the atrophic signaling pathways that have been hypothesized to exist. As a first effort to test this hypothesis, we identified genes that were significantly induced (P < 0.05) at TAC-R1 but did not show changes in expression in the TAC1 or TAC14 ventricles. The selected genes and their fold-induction over sham-operated controls are shown in Table 1.


Figure 2
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  		Fig. 2. Clustering of gene expression. Clustered gene expression patterns of 9,911 genes are shown graphically. Each row represents a different gene, and each column displays gene expressions at each point (TAC1, TAC14, and TAC-R1). Data values are plotted as log(2)-fold change vs. sham-operated control. Data values displayed as red and green represent elevated and reduced expression, respectively.

 

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  		Table 1. Regression-specific genes

 
Confirmation of expression changes.
To confirm the validity of our DNA microarray data, we performed qRT-PCR with six representative genes from the functional categories among the isolated 52 genes (Fig. 3). The expression changes assayed by qRT-PCR generally agreed with the changes determined by DNA microarray.


Figure 3
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  		Fig. 3. Quantitative real-time PCR (qRT-PCR) of selected representative genes. qRT-PCR was performed in triplicate with 3 independent heart samples at each point (TAC1, TAC14, and TAC-R1). The expression was presented as fold-induction over sham (n = 3). *P < 0.05 vs. sham group.

 
eya2 as a negative regulator of cardiac hypertrophy.
Among the isolated genes, eya2 was of particular interest. eya2 is a transcription coactivator, acting through interaction with transcription factor SIX proteins, which may activate genetic programs during limb development, myogenesis, and ovarian cancer development (9, 26, 29). We postulated that eya2 plays an essential role during regression of cardiac hypertrophy by activating regression-associated downstream genes. To test this hypothesis, an eya2-expressing recombinant adenovirus, AdEya2, was generated. By Western blotting, we confirmed that Eya2 protein is expressed in cardiomyocytes transfected with AdEya2, but not in nontransfected cardiomyocytes or in cardiomyocytes transfected with a control adenovirus, AdLacZ (Fig. 4A). Untransfected or transfected cardiomyocytes were cultured for 24 h and were then further stimulated with phenylephrine (PE) for 24 h. Pronounced sarcomeric rearrangement was observed in response to the hypertrophic stimulation as detected by immunostaining with antiactinin antibody. Unlike the nontransfected or AdLacZ-transfected cardiomyocytes, the AdEya2-transfected cardiomyocytes lacked prominent sarcomeric structures after PE treatment (Fig. 4B). PE treatment significantly increased the size of AdLacZ-transfected cardiomyocytes, as assessed by measuring the surface area of the cells under a microscope. In contrast, no significant PE-induced increase in cell size was observed with the AdEya2-transfected cardiomyocytes (Fig. 4C). ANF and ß-myosin heavy chain (MHC) are typical markers for cardiac hypertrophy. PE treatment induced approximately two- to threefold increases in the ANF and ß-MHC expression in AdLacZ-transfected cardiomyocytes. However, AdEya2 transfection completely blocked elevated ANF and ß-MHC expression (Fig. 4D). Taken together, these results suggested that Eya2 is a transcriptional coactivator involved in atrophic signaling pathway.


Figure 4
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  		Fig. 4. Effects of Eyes absent 2 (Eya2) on the morphological and biological changes induced by phenylephrine (PE) in cultured neonatal rat cardiomyocytes. A: transfection of AdLacZ and AdEya2 to cultured neonatal cardiomyocytes was analyzed by Western blotting. The putative Eya2 protein (arrowhead) was detected only in the AdEya2-transfected cells. B: sarcomeric organization of the cardiomyocytes was visualized by staining with antiactinin antibody. Marked sarcomeric reorganization was observed in response to PE treatment. The response was completely ablated by AdEya2 transfection. C: cell surface areas of the cardiomyocytes were measured using Image J software (n = 100). Shown are the mean area values ± SD. *P < 0.05 vs. control. D: AdEya2 transfection inhibits PE-induced ANF and ß-myosin heavy chain (MHC) expression. *P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality (14). Although it is regarded initially beneficial, sustained cardiac hypertrophy leads to systolic and diastolic dysfunction and ultimately the development of heart failure (12). Intensive efforts have been focused on deciphering intracellular signaling pathways mediating cardiac hypertrophy in an attempt to design novel therapeutic strategies that may intervene in these responses. In recent years, several negative regulators counteracting cardiac hypertrophy have been identified (8). Modulating these negative regulators may provide alternative strategies for treatment of heart failure.

In this study, we performed DNA microarray gene profiling to identify altered gene expression during regression of pressure overload-induced cardiac hypertrophy. We hypothesized that some of the genes upregulated during the regression period might be involved in either negating the positive hypertrophic signaling pathways or triggering the atrophic signaling pathways that have been hypothesized to exist. Thus, we hoped to identify additional novel negative regulators of cardiac hypertrophy and obtain an indication of whether the suggested atrophic signaling pathways are present. Augmenting the atrophic signaling pathways, if they indeed exist, would provide another alternative means for control of detrimental remodeling during cardiac hypertrophy.

We utilized a surgical model for the regression of cardiac hypertrophy in which aortic constriction is relieved after significant hypertrophy has developed. We observed a rather rapid reversal of cardiac hypertrophy, as judged by changes at both the cellular and molecular levels. Unlike the pharmacological model of cardiac hypertrophy (6), this surgical model is not confounded by the pressure-independent systemic effects of drugs. Detailed hemodynamic, histological, and molecular assessment associated with the development of cardiac hypertrophy and its regression in a similar murine surgical model has been previously reported (7).

Among the 9,911 transcripts probed, we identified 52 genes that are specifically upregulated during the regression period. While the role of most of these genes in cardiac hypertrophy is not known, eya were of particular interest.

The eya gene was first identified from the studies of Drosophila eye development. While loss of function of eya typically leads to loss of the entire eye, directed expression of eya leads to the formation of ectopic eyes (2). There are four vertebrate eya homlogs, eya1–4 (27). eya1 is responsible for branchio-oto-renal syndrome, an autosomal dominant disease characterized by branchial arch abnormalities, hearing loss, and kidney defects (1, 30). Mutations in eya4 cause an autosomal dominant syndrome characterized by dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (23). No association of eya2 and eya3 with any human disease has yet been reported. Eya proteins are transcriptional coactivators defined by a variable amino-terminal domain with transactivating activity and a highly conserved carboxy-terminal domain that mediates interactions with other transcriptional coactivators such as SIX and DACH (15, 19, 24). Although a few target genes of Eya have been identified, their potential role in cardiac remodeling is unclear (18). Since Eya2 is a positive transcriptional coactivator and is upregulated during the regression period, we hypothesized that Eya2-mediated reprogramming of gene expression might be associated with the regression of cardiac hypertrophy. This yet-to-be characterized signaling pathway might correspond to at least part of previously hypothesized atrophic signaling pathways. As preliminary data supporting this hypothesis, we report here that adenovirus-mediated overexpression of Eya2 in rat neonatal cardiomyocytes blocks the PE-induced cardiomyocyte hypertrophy. To further elucidate the molecular mechanism underlying the inhibitory activity of Eya2, more target genes of Eya2 should be identified by microarray and chromatin immunoprecipitation analyses and tested for their roles in cardiac remodeling. It would be also important to determine whether Eya2 is an inhibitor or regressor of cardiac hypertrophy.

Our data in this study suggest that regression of cardiac hypertrophy is associated with upregulation of negative regulators of cardiac hypertrophy and positive regulators of yet-to-be-identified cardiac atrophic signaling pathways. DNA microarray analysis with whole genome chips and a proteomics approach are under way to obtain more insight into the hypothesized atrophic signaling pathways.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
During this work, W. J. Park was supported by a Global Research Laboratory Program (M6-0605-00-0001) from the Korean Ministry of Science and Technology, and Korean Ministry of Health and Welfare Grant A050472. D. H. Kim was supported by Systems Biology Research Grant M1-0309-00-0006 from the Korean Ministry of Science and Technology. R. J. Hajjar and W. J. Park were supported by National Heart, Lung, and Blood Institute Grant HL-080498-01.


   FOOTNOTES
 
Address for reprint requests and other correspondence: W. J. Park, Dept. of Life Science, Gwangju Inst. of Science and Technology (GIST), 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea (e-mail: wjpark{at}gist.ac.kr).

Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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