(Circulation. 2001;103:730.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Pressure Overload Increases GATA4 Binding Activity via Endothelin-1
From the Departments of Pharmacology and Toxicology and Physiology (O.V.), Biocenter Oulu, University of Oulu, Finland.
Correspondence to Heikki Ruskoaho, MD, PhD, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, PO Box 5000, FIN-90014, University of Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi
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Abstract |
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Background—The signaling cascades responsible for the activation of transcription factors in the hypertrophic growth of cardiac myocytes during hemodynamic overload are largely unknown. Several of the genes upregulated in the hypertrophied heart, including B-type natriuretic peptide (BNP) gene, are controlled by the cardiac-restricted zinc finger transcription factor GATA4.
Methods and Results—An in vivo model of intravenous administration of arginine8-vasopressin (AVP) for up to 4 hours in conscious normotensive rats was used to study the signaling mechanisms for GATA activation in response to pressure overload. Gel mobility shift assays were used to analyze the trans-acting factors that interact with the GATA motifs of the BNP promoter. AVP-induced increase in mean arterial pressure was followed by a significant increase in the BNP and c-fos mRNA levels in both the endocardial and epicardial layers of the left ventricle, whereas GATA4 and GATA6 mRNA levels remained unchanged. Pressure overload within 15 to 60 minutes produced an increase in left ventricular BNP GATA4 but not GATA5 and GATA6 binding activity, and at 30 minutes a 2.2-fold increase (P<0.001) in GATA4 binding was noted. The mixed endothelin-1 ETA/ETB receptor antagonist bosentan but not the angiotensin II type 1 receptor antagonist losartan completely inhibited the pressure overload–induced increase in left ventricular BNP GATA4 binding activity. Bosentan alone had no statistically significant effect on GATA4 binding activity of the left ventricle in conscious animals.
Conclusions—ET-1 is a signaling molecule that rapidly upregulates GATA4 DNA binding activity in response to pressure overload in vivo.
Key Words: hypertrophy • blood pressure • natriuretic peptides • genes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The heart adapts to increased demands for cardiac work by increasing muscle mass through the initiation of a hypertrophic response, which may be a consequence of alterations in specific signaling molecules and their downstream pathways in individual myocytes. Accordingly, identifying the signals that mediate the pathways from biomechanical stress to downstream cellular events is a major area of research interest.1 2 3 Both myocytes and nonmyocytes are direct biomechanical sensors of hemodynamic load.4 5 Growth signals are generated by the release of growth factors and cytokines, which lead to a regionally localized response. The factors that have been implicated in this response include peptides that stimulate G protein–coupled receptors, such as endothelin-1 (ET-1) and angiotensin II (Ang II).2 3 According to in vitro results, the primary downstream effectors are the mitogen-activated protein kinases (MAPKs), including the extracellular signal–regulated kinases (ERKs), the Jun N-terminal kinases (JNKs), and the p38 MAPKs.6
At the genetic level, hemodynamic overload is associated
with rapid (within 1 hour) and transient upregulation of
immediate-early genes that encode transcription factors
(c-fos,
c-jun, and
Egr-1).7
B-type natriuretic peptide (BNP) is also expressed at this early
stage.8 9 In the
medium term (12 to 24 hours), cardiomyocytes activate the fetal gene
regulatory program with reexpression of genes for atrial natriuretic
peptide (ANP), skeletal muscle 
-actin, and ß-myosin heavy
chain
(ß-MHC).2 7 10 11
Several of the genes upregulated during hypertrophy are controlled by
the cardiac-restricted zinc finger transcription factor
GATA4,12 13 14
and recent work has shown that GATA binding sites appear to be required
for activation of ß-MHC
expression15 and Ang II type
1a (AT1A) receptor
expression16 in response to
pressure-overload hypertrophy in rats. Binding on
AT1A receptor and BNP GATA sites in extracts of
hypertrophied but not control hearts was also
noted,16 suggesting that
GATA binding activity is enhanced in the hypertrophied myocardium. The
signaling cascades that affect GATA4 either in vitro or in vivo,
however, are not known.
In the present study, to characterize the time course of induction of cardiac GATA activity, we measured hemodynamics and left ventricular GATA mRNA levels and BNP GATA binding activity at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after pressure overload produced by intravenous infusion of arginine8-vasopressin (AVP) in conscious normotensive rats. We also assessed the effects of the mixed ETA/ETB receptor antagonist bosentan and the AT1 receptor antagonist losartan on the increase of BNP GATA binding activity to determine whether ET-1 or Ang II plays a causal role in the induction of GATA DNA binding activity by pressure overload in ventricles. Furthermore, the actions of ET-1 and Ang II receptor antagonism on BNP GATA activity under basal conditions (without pressure overload) in conscious rats as well as ET-1 and bosentan effects in myocyte cultures were analyzed.
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Methods |
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Materials
Bosentan was from F. Hoffmann–La Roche Ltd, Basel, and Actelion Ltd, Allschwil, Switzerland (Dr Martine Clozel) and losartan from DuPont Merck Pharmaceutical Company, Wilmington, Del (Dr Ronald D. Smith).
Experimental Design in Conscious Rats
The 2-month-old Sprague-Dawley rats were instrumented
as previously described.9 The
experiments were started by measurement of mean arterial pressure (MAP)
and heart rate in the conscious rats for 30 minutes before baseline
hemodynamic measurements were made. Then, AVP (Peninsula Laboratories
Europe, 0.05
µg · kg-1 · min-1
IV) or vehicle (0.9% NaCl IV) was infused at 37.5 µL/min for 15
minutes, 30 minutes, 1 hour, 2 hours and 4 hours. In a separate series
of experiments, bosentan (10 mg/kg), losartan (10 mg/kg), or vehicle
(0.9% NaCl) was injected as an intravenous bolus (injection volume 0.1
mL/100 g body wt), followed by 30 minutes of vehicle or AVP infusion.
Left ventricles and right atria were prepared for the mRNA
determinations and gel mobility shift assays at the end of infusions as
previously described.9 The
experimental design was approved by the Animal Use and Care Committee
of the University of Oulu.
Cell Culture
Myocytes were prepared from 1- to 3-day-old neonatal
rat hearts as described
earlier.17 After 48 hours of
incubation in complete serum-free medium
(CSFM),17 the medium was
replaced with CSFM or CSFM supplemented with ET-1 100
nmol/L18 or bosentan 10
µmol/L for 15 minutes, 30 minutes, 1 hour, and 4
hours.
Gel Mobility Shift Assays
Nuclear extracts were prepared from atrial and
ventricular tissue of AVP- or vehicle-infused rats and from neonatal
rat myocytes as described
previously.19 20
Double-stranded synthetic oligonucleotides containing GATA
(5'-TGTGTCTGATAAATCAGAGATAAC-CCCACC-3')
or AP-1
(5'-GGAAGTGTTTTTGATGAGTCACC-CCA-3')
motifs of the rat BNP promoter were labeled with
[-32P]dCTP. Binding reactions contained
30 µg of crude nuclear extract or 6 µg of nuclear extract from
cardiac myocytes and 2 µg of poly-(dI-dC) · (dI-dC) in a buffer
containing (in mmol/L) HEPES 10 (pH 7.9), MgCl2
1, KCl 50, DTT 1, EDTA 0.1, and PMSF 0.25; 10% glycerol; 0.025%
NP-40; and 1 µmol/L each of aprotinin, leupeptin, and pepstatin; and
when appropriate, various molar excesses of unlabeled double-stranded
oligonucleotides. Reactions were carried out at room temperature for 20
minutes, and protein-DNA complexes were separated by electrophoresis on
5% polyacrylamide gel in 0.5x TBE (Tris-borate-EDTA buffer) at 4°C.
Nonlabeled double-stranded oligonucleotides corresponding to GATA or
AP-1 binding sites of the BNP promoter and a GATA consensus sequence
(Santa Cruz Biotechnology) were used as specific competitor DNAs.
Nonspecific competitor DNAs included a double-stranded oligo carrying
the mutated binding site for GATA4
(5'-TGTGTCTGGTAAATCAGA
GGTAACCCCACC-3') and Oct-1 as
nonrelated DNA. For supershift experiments, 1 µg of goat polyclonal
GATA4, GATA5, GATA6, c-Fos(4)-G, c-Fos(K-25)-G, c-Jun/AP-1(N)-G, Jun
B(N-17)-G, or Jun D(329)-G affinity-purified IgG (Santa Cruz
Biotechnology) were used.
Isolation and Analysis of RNA
RNA was isolated by the guanidine thiocyanate–CsCl
method.9 For the RNA Northern
blot analysis, 20-µg samples of RNA from the ventricles were
separated by electrophoresis and transferred to nylon membranes. A
390-bp fragment of rat BNP
cDNA,21 cDNA probes for rat
GATA4 (1417 bp), GATA6 (1175 bp),
c-fos (1050 bp), and GAPDH and
an oligonucleotide probe complementary to rat 18S ribosomal RNA were
labeled, and the membranes were hybridized as described
previously.9
BNP Radioimmunoassay
The BNP radioimmunoassay was performed as previously
described.9 The sensitivity
of the assay was 2 fmol/tube, and 50% displacements of the respective
standard curve occurred at 25 fmol/tube. The intra-assay and interassay
variations were <10% and <15%, respectively. Serial dilutions of
the tissue extracts showed parallelism with the standards. Tissue BNP
is expressed as a concentration per milligram wet
weight.
Statistics
The results are expressed as mean±SEM. For the
comparison of statistical significance between 2 groups, Student’s
t test was used. The
hemodynamic variables were analyzed with 1-way ANOVA, followed by
Student-Newman-Keuls post hoc test. A value of
P<0.05 was considered
statistically significant.
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Results |
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Characterization of Pressure-Overload Model
To study the signaling cascades responsible for the activation of transcription factors during pressure overload, an in vivo model of intravenous administration of AVP for up to 4 hours in conscious normotensive rats was used.8 9 MAP rose rapidly and reached maximum value within 15 minutes during AVP infusion, associated with a significant decrease in heart rate (Figure 1
). The AVP-induced increase in blood pressure was
followed by an increase in the BNP mRNA levels in both the epicardial
and endocardial layers of the left ventricle
(Figure 2A). A 1.7-fold and 3.5-fold increase in left
ventricular endocardial BNP mRNA levels was noted after 1 and 4 hours
of AVP infusion, respectively
(Figure 2B). The rapid activation of BNP mRNA gene expression
resulted in a significant increase in left ventricular endocardial
immunoreactive BNP peptide levels at 2 (from 167±14 to 260±12 pmol/g,
P<0.001) and 4 (from 193±13
to 332±10 pmol/g, P<0.001)
hours of AVP infusion. Under these experimental conditions, AVP
infusion has no effect on right atrial BNP mRNA levels and right atrial
pressure,8 supporting the
hypothesis that AVP has no direct effect on cardiac BNP gene
expression.
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Pressure Overload Upregulates Left Ventricular
GATA Binding Activity
Gel mobility shift assays were used to analyze the
trans-acting factors that
interact with the GATA or AP-1 motifs of the BNP promoter. AVP infusion
for 15 minutes increased DNA binding activity in left ventricular
extracts with a 30-bp double-stranded oligonucleotide probe containing
the -90 BNP GATA sites (rBNP-90 GATA probe), and at 30 minutes, a
2.2-fold increase (from 1.96±0.27 to 4.33±0.75 arbitrary
densitometric units, P<0.001)
was noted
(Figure 3A). The BNP GATA binding activity also increased in
response to 1-hour AVP infusion, whereas at 2 or 4 hours, BNP GATA
binding activity remained unchanged. Furthermore, AVP infusion for 15
minutes to 4 hours had no significant effect on DNA binding activity in
right atrial nuclear extracts (at 30 minutes: 3.60±2.51 versus
4.55±3.03 arbitrary densitometric units,
P=NS, n=6), suggesting that the
observed changes in BNP GATA binding activity are related to
hemodynamic effects of AVP.
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To determine the specificity of ventricular GATA binding
activity, competition analyses were performed
(Figure 3B
). The formation of complexes with the rBNP-90 GATA
probe was effectively inhibited by the unlabeled self
(Figure 3B, lanes 2 to 4) and GATA consensus DNA
(Figure 3B, lane7), indicating that the DNA-protein complex
was the result of a specific interaction. The binding was unaffected by
an excess of oligonucleotides corresponding to the nonrelated
competitor DNA Oct-1
(Figure 3B, lane 5) or the mutated BNP GATA site
(Figure 3B, lane 6). To further confirm that the complex
bound to the BNP GATA site contains GATA proteins, supershift assays
were carried out using GATA4
(Figure 3C, lanes 3 and 4), GATA5
(Figure 3C, lanes 5 and 6), and GATA6
(Figure 3C, lanes 7 and 8) antibodies. Experiments using rat
ventricular extracts from vehicle- or AVP-infused rats clearly showed
antibody-induced supershift of the GATA4 but not GATA5 or GATA6
complexes.
Unlike GATA4, the level of BNP AP-1 binding activity was not
increased in nuclear extracts from the vehicle- and AVP-infused rat
hearts within 15 minutes to 4 hours
(Figure 3A). Weak supershifts were observed with JunB (N-17)
and JunD (329) antibodies, which demonstrate the presence of JunB and
JunD in the complex formed between the BNP AP-1 site and proteins in
AVP-infused rat heart nuclear extracts (data not shown), as reported
previously in extracts from rat hearts 2 days after
coarctation.16
GATA4, GATA6, and c-fos mRNA Levels
We next examined the possibility that the increase in
GATA activity could result from an increase in the expression of the
GATA4 gene itself or an increase in the stability of the message.
Northern blot analysis with both rat GATA4 and GATA6 probes identified
a single 3.3-kb and 1.8-kb mRNA species, respectively, in the
ventricles of adult rats. Pressure overload had no effect on left
ventricular GATA4 or GATA6 mRNA levels during 15-minute to 4-hour AVP
infusions
(Figure 2A and 2B). In contrast, expression of
c-fos mRNA, which is another
early hallmark of the hypertrophic
response,22 increased
markedly in response to pressure overload
(Figure 2A).
Pressure Overload–Induced Upregulation of
GATA4 Binding Activity is Inhibited by the ET-1 Receptor
Antagonist
To identify the mechanism by which pressure overload
increases GATA4 binding activity, the roles of ET-1 and Ang II were
evaluated in a series of experiments in which bosentan and losartan
injections were used. When nuclear extracts from bosentan- and bosentan
plus AVP–infused rat ventricles were used in gel mobility shift
reactions containing the labeled rBNP-90 GATA probe, specific complexes
were obtained
(Figure 4A). The pressure overload–induced increase in GATA
binding activity was completely inhibited by the mixed
ETA/ETB receptor
antagonist bosentan
(Figure 4A and 4B), whereas the AT1
receptor antagonist losartan had no inhibitory effect on BNP GATA
binding activity (data not shown). Bosentan alone had no statistically
significant effect on BNP GATA binding activity
(Figure 4A and 4B). Previously, we showed that in conscious
rats, bosentan at a dose of 10 mg/kg IV completely blocked any increase
in MAP produced by big ET-1 infusion and losartan at a concentration of
10 mg/kg completely blocked any increase in MAP produced by Ang II
infusion.9 Furthermore,
injections of bosentan and losartan did not significantly alter the
hemodynamic responses evoked by AVP infusion (data not
shown9 ), thus allowing us to
examine the direct action of load versus a requirement for ET-1 and Ang
II to mediate pressure overload–induced increase in GATA binding
activity.
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ET-1 Increases GATA Binding Activity in
Neonatal Cardiac Myocytes
The specific complexes were observed in gel mobility
shift assays of nuclear extracts prepared from cultured rat neonatal
cardiomyocytes. As shown in
Figure 4C, ET-1 treatment for 15 to 60 minutes produced an
increase in DNA binding activity using rBNP-90 GATA probe. This rapid
increase in BNP GATA binding activity in cultured cardiomyocytes was
inhibited by the mixed
ETA/ETB antagonist
bosentan
(Figure 4C, lane 6). GATA4 mRNA levels remained unchanged in
ET-1–treated cultured cardiac myocytes
(Figure 4D).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although numerous transcription factors have been implicated in the activation of cardiac genes in response to hypertrophy,1 3 13 14 how hypertrophic signal transduction pathways are linked to changes in cardiac gene expression is not known. The transcription factors GATA4, -5, and -6 have been shown to activate numerous hypertrophic marker genes13 15 containing GATA binding sites required for cardiac-specific expression. It has also been shown that GATA4 DNA binding activity is upregulated in hypertrophied rat hearts 7 days after aortic coarctation.16 We have previously documented that acute pressure overload produced by AVP infusion is a potent activator of BNP gene expression in the adult rat heart.9 The present study extends those findings by demonstrating that (1) ventricular BNP GATA4 but not GATA5 and GATA6 binding is activated at a very early stage of pressure overload, well before the development of left ventricular hypertrophy; and (2) the activation of the endothelin signaling pathway plays an important role in mediating pressure overload–dependent GATA4 binding activation.
The mechanisms by which pressure overload is transduced by the cardiac muscle cell and translated into myocyte hypertrophic response remain only partially understood. At the cellular level, hypertrophy is thought to develop in response to a combination of mechanical (hemodynamic load) and neurohumoral stimuli, such as Ang II, ET-1, and adrenergic agents.4 5 It has been reported that mechanical stretch is coupled with cellular release of Ang II and ET-1 and that they act as chemical mediators of stretch-induced myocyte hypertrophy in cultured rat cardiomyocytes.23 24 The production of ET-1 has also been shown to increase in the hypertrophied rat heart in various models of pressure overload.25 26 27 Thus, endogenous cardiac production of ET-1 may play a functional role in mechanical load–induced cardiac gene expression.
A key finding of the present study was that the rapid increase in GATA4 binding activity in cardiac nuclear extracts in response to pressure overload is mediated by ET-1 but not Ang II. The source of ET-1 in the heart may be myocytes or nonmyocytes. It has been shown that endothelial cells to some extent contain stores of ET-1,28 29 and when endothelial cells in culture are stretched, ET-1 can be released rapidly.28 In addition, mRNA levels of ET-1 increase by stretching of cardiac myocytes,24 ET-1 receptor antagonists decrease hemodynamic load–induced ANP release in vivo,30 and mechanical strain induces human BNP promoter activity in vitro.31 Thus, pressure-overload stimulus, by increasing wall stress, appears to release ET-1 from preformed stores, which then participates in the regulation of GATA4 binding activity. In the present study, the increase in GATA4 binding activity was transient, suggesting that cardiac ET-1 stores may be limited. Whether ET-1 is also involved in controlling GATA4 binding activity in chronic pressure overload in vivo remains to be determined.
Several signaling pathways, including intracellular calcium, protein kinase C, nonreceptor protein tyrosine kinases, and calcineurin, may be involved in the initiation and maintenance of myocyte hypertrophy.3 6 32 There is also considerable evidence that activation of any of the 3 MAPK cascades can lead to a hypertrophic response in myocytes and that these MAPK subfamilies are activated by ET-1.18 33 The activation of ERK, JNK, and p38 MAPK has been demonstrated after the application of mechanical strain in cultured myocytes.32 34 35 36 Using neonatal rat ventricular myocytes, we found that SB-203580, a potent p38 MAPK inhibitor, inhibited the ET-1–induced increase in BNP GATA4 binding activity (R. Kerkelä, S. Pikkarainen, N. Hautala, H. Ruskoaho, unpublished observation). This result, together with the observation that the p38 MAPK accounted for 50% of the human BNP promoter strain response in neonatal rat ventricular myocyte cultures,36 suggests that the p38 MAPK pathway might also mediate the early increase of GATA4 activity in pressure overload in vivo.
Previous studies have shown that the activation of rat BNP
promoter in cardiac myocytes required GATA binding sites in the
promoter.37 Furthermore,
mechanical strain stimulates the activity of a transfected human BNP
gene promoter in neonatal rat ventricular
myocytes,38 and this
stimulation appears to be derived in part from a direct effect on the
cardiac myocyte and in part from an autocrine/paracrine pathway that
involves the sequential generation of Ang II and
ET-1.31 However, the
inability of the ET-receptor antagonist bosentan to inhibit the early
activation of ventricular BNP gene expression in response to pressure
overload in vivo9 suggests
that there is a requirement for additional transcription factors that
probably act in concert with GATA4 to activate BNP gene expression. In
vitro, other transcription factors, such as
NF-
B36 and
NF-AT,39 are also important
for BNP gene expression, and recent work has suggested that ANP
expression may be regulated by cooperative interaction of
cis-acting elements with
GATA4 and Csx/Nkx2.5.40 The
potential interaction of these transcription factors with GATA4 in
promoting the changes in cardiac gene expression during pressure
overload represents a logical target for future study.
In conclusion, this study shows for the first time that ET-1 acts as a mediator of GATA4 binding activity in pressure overload. This may represent a new mechanism for transduction of extrinsic hypertrophic signals to the nucleus in pressure-overload hypertrophy as well as in other pathophysiological conditions associated with high ET-1 activity, such as heart failure and myocardial ischemia.
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Acknowledgments |
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This work was supported by grants from the Academy of Finland, the Sigfrid Juselius Foundation, and the Finnish Foundation for Cardiovascular Research. We thank Marja Arbelius, Pirjo Korpi, Tuula Lumijärvi, and Sirpa Rutanen for their expert technical assistance.
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Footnotes |
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Guest Editor for this article was Wilson S. Colucci, MD, Boston University Medical Center, Boston, Mass.
Received May 22, 2000; revision received July 26, 2000; accepted August 14, 2000.
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