(Hypertension. 2000;36:48.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Cardiac Ankyrin Repeat Protein Is a Novel Marker of Cardiac Hypertrophy
Role of M-CAT Element Within the Promoter
From the Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Correspondence to Masahiko Kurabayashi, MD, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail mkuraba{at}pop.med.gunma-u.ac.jp
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Abstract—CARP, a cardiac doxorubicin (adriamycin)-responsive protein, has been identified as a nuclear protein whose expression is downregulated in response to doxorubicin. In the present study, we tested the hypothesis that CARP serves as a reliable genetic marker of cardiac hypertrophy in vivo and in vitro. CARP expression was markedly increased in 3 distinct models of cardiac hypertrophy in rats: constriction of abdominal aorta, spontaneously hypertensive rats, and Dahl salt-sensitive rats. In addition, we found that CARP mRNA levels correlate very strongly with the brain natriuretic peptide mRNA levels in Dahl rats. Transient transfection assays into primary cultures of neonatal rat cardiac myocytes indicate that transcription from the CARP and brain natriuretic peptide promoters is stimulated by overexpression of p38 and Rac1, components of the stress-activated mitogen-activated protein kinase pathways. Mutation analysis and electrophoretic mobility shift assays indicated that the M-CAT element can serve as a binding site for nuclear factors, and this element is important for the induction of CARP promoter activity by p38 and Rac1. Thus, our data suggest that M-CAT element is responsible for the regulation of the CARP gene in response to the activation of stress-responsive mitogen-activated protein kinase pathways. Moreover, given that activation of these pathways is associated with cardiac hypertrophy, we propose that CARP represents a novel genetic marker of cardiac hypertrophy.
Key Words: doxorubicin • proteins • hypertrophy, cardiac • brain • natriuretic peptides • protein kinases
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Introduction |
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In response to hemodynamic overload, several parallel and interconnected intracellular signal transduction cascades are activated and mediate their biological effects, which include cardiac hypertrophy.1 These intracellular pathways also activate transcription factors such as c-fos, c-jun, c-myc, and egr-1, which in turn regulate many genes involved in diverse cellular metabolisms, including myocardial growth and apoptosis.2 However, the induction of these genes in response to acute mechanical loading is transient, and the precise role of immediate-early response genes in the ongoing development of hypertrophy and progression to heart failure remains obscure.
Altered gene expression during a longer time course in response to cardiac hypertrophy or heart failure is characterized by the increase in the expression of the constitutive contractile proteins, natriuretic peptides (eg, atrial natriuretic peptide [ANP]), brain natriuretic peptide [BNP]), the growth factors, and their receptors, adrenergic receptors, and other receptors.3 Previous studies implicated the expression of ANP and BNP genes as a marker for ventricular dysfunction.4 Although the molecular mechanisms responsible for the upregulation of these peptides have not been fully understood, nuclear factors whose expression levels are closely associated with the cardiac function may be candidates for regulatory molecules involved in such a process.
By using the differential display methods of mRNAs expressed at distinct levels between control and doxorubicin-treated cardiac myocytes, Jeyaseelan et al5 identified CARP as a cardiac doxorubicin (adriamycin)-responsive protein whose mRNA levels are markedly downregulated by doxorubicin. By in situ hybridization in developing mouse embryo, they demonstrated that CARP mRNA is specifically expressed in the heart. Deduced amino acid sequence of CARP cDNA revealed 4 repeats of ankyrin motif, which appears to be involved in protein-protein interactions. In fact, Zou et al6 identified the same molecule by 2-hybrid screening, in which the authors used HF1a-binding protein YB-1 as bait. In the present study, we examined CARP expression during cardiac hypertrophy and tested the hypothesis that CARP can serves as a genetic marker of cardiac hypertrophy.
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Methods |
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Animals
All procedures were approved by the Animal Care and Use Committee of Gunma University School of Medicine and were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the National Research Council. Male Wistar-Kyoto (WKY) rats (250 to 300 g, 15 to 16 weeks old; n=7) and spontaneously hypertensive rats (SHR) (250 to 300g, 15 to 16 weeks old; n=7; Imai) were housed under climate-controlled conditions. Pressure overload was produced with abdominal aortic constriction (sham-operated n=6, pressure overloaded n=18) as previously described.7 The Dahl salt-sensitive (DS) rats were supplied by Eizai Pharmaceutical Company. Male DS rats were fed a 0.3% NaCl (low-salt) diet after weaning until the age of 6 weeks, after which they were fed an 8% NaCl (high-salt) diet as previously described8 (7 rats at 6 weeks of age, 12 rats at 11 weeks of age, 8 rats at 18 weeks of age). Systolic blood pressure (SBP) was recorded in awake rats with tail-cuff sphygmomanometry (model UR5000; Ueda).
RNA Extraction and Northern Blot Analysis
Total RNA and Northern blot analyses were conducted as
described previously.9 Radiolabeling of the probes, a 1-kb
fragment of rat CARP cDNA sequence (courtesy of Dr L. Kedes, Institute
of Genetic Medicine, University of Southern California, Los Angeles,
Calif) and a 628-bp fragment of rat BNP cDNA sequence10
(courtesy of Dr K. Kangawa, National Cardiovascular
Center, Suita, Japan), was performed with a Boehringer-Mannheim
random primer labeling kit.
Plasmid Constructions
Expression vector RSV/p38 (kindly provided by Jiahuai Han, The
Scripps Research Institute, La Jolla, Calif) and EXVRacV12 (kindly
provided by Michael Karin, University of California San Diego) have
been described elsewhere.11 12 13
Human genomic clone that encodes CARP was isolated by screening the
human leukocyte genomic library (HL1006d; Clontech) with the
32P-labeled rat CARP cDNA.5 For the
generation of luciferase reporter genes, the forward primers with a
KpnI site (underlined) (-1832Luc,
5'-GGGGGGGTACCTGCAGCAAGT-TACTTAATG-3'; -206Luc,
5'-AGAAAGGTACCACTGGGGG-TGTGA-3') were used in a PCR with
a plasmid containing a 
5-kb DNA insert as a template with the
reverse primer (nucleotide +170) with an XhoI
site (underlined) (5'-GCAGATCTCGAGGGGGGGC-CCCTC-3'). PCR
products were subcloned into the KpnI/XhoI
sites of the promoterless luciferase reporter gene vector pGL3
(Promega).
For the generation of site-directed mutants of an M-CAT element in the CARP promoter, recombinant PCR with 2 rounds of amplification was performed. The PCR primers (mutations of wild-type sequence appear in bold) for M-CAT mutation were 5'-ACCAAGAAGGCGGCCCTC-3' (sense) and 5'-GAGGGCC-GCCTTCTTGGT-3' (antisense). In brief, sense and antisense primers with the corresponding mutations were synthesized and incubated in separate reaction tubes with -1832Luc as template, upstream primer (nucleotide -206), and reverse primer (nucleotide +170), thus yielding 2 subfragments that each contained the appropriate mutation. Subfragments were gel purified, and a second round of PCR was performed with upstream primer (nucleotide -206) and reverse primer (nucleotide +170). The PCR products were then isolated and subcloned into the KpnI/XhoI sites of pGL3 as described. The resultant plasmid was designated as CARP-206(MCATmut)Luc. For the rat BNP promoter-luciferase reporter construct, which contains sequence from -1000 to +70 of the rat BNP gene, 2 oligonucleotide primers were designed based on the published sequence14 : the 5'-primer with the KpnI site (underlined) was 5'-CCCGGTACCAGTCTCATTTCTCACCTGAGTGGGAGA-3', and the 3'-primer with the XhoI site (underlined) was 5'-GGGCTCGAGGCAGCTGCGATGGTGTCCTGC-3'. The PCR was performed using the rat liver genomic DNA as a template. The PCR product was subcloned into the KpnI/XhoI sites of pGL3. All resultant plasmids were verified with sequencing.
Electrophoretic Mobility Shift Assay
Nuclear extracts from neonatal rat cardiac myocytes were
prepared as previously described.15 The sequences of the
sense strand of double-stranded oligonucleotides used
as probes or competitors in electrophoretic mobility shift assays
(EMSAs) were as follows, with a consensus motif underlined and
mutations of wild-type sequence in bold: CARP(-42/-25),
5'-ACCAAAGGAATGGCCCTC-3'; CARP(-42/-25 mol/L),
5'-ACCAAGAAGGCGGCCCTC-3', and BNP(-113/-95),
5'-CAGGCAGG-AATGTGTCTGA-3'. Binding reactions were
performed as previously described.16
Cell Culture and DNA Transfection and Luciferase Assay
Neonatal rat ventricular myocytes were isolated from
1-day-old WKY rats as previously described.17 Cells
were transfected with 1 µg reporter plasmid and 1 µg expression
plasmid with Tfx-50 (Promega) according to the manufacturer’s
procedure. After transfection, cultures were refed with DMEM containing
10% fetal calf serum. Luciferase assays were performed as described
previously.16 SB203580 was purchased from Calbiochem.
Data Analysis
Statistical analysis were performed by a Student’s
t test with significant differences determined as
P<0.05. Correlation was performed with the use of simple
regression analysis.
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Results |
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An Increase in CARP mRNA Levels During Cardiac Hypertrophy Induced by Acute or Chronic Pressure Overload
To determine whether cardiac hypertrophy affects CARP mRNA levels, we performed Northern blot analysis and quantified the mRNA levels in the heart subjected to acute pressure overload by constricting the rat abdominal aorta. CARP mRNA levels were significantly increased by 2.7±0.24-fold in the pressure-overloaded hearts (control versus pressure overload, P<0.01) (Figures 1A and 1B). In agreement with the previous reports, BNP mRNA levels were markedly induced by pressure overload.18 We next performed Northern blot analysis of total RNA of the rat left ventricle at various developmental stages from fetus to adult to determine whether the CARP gene is considered to be a fetal gene. The results showed that CARP mRNA levels in the heart gradually increase during development (Figure 1C) in a manner similar to BNP mRNA levels. We further determined whether cardiac hypertrophy associated with chronic elevation of blood pressure affects CARP expression. At the age of 15 to 16 weeks, SHR showed a significant elevation in SBP compared with WKY rats (SHR versus WKY rats, P<0.01) (Figure 1D). CARP mRNA levels were 1.6 times higher in SHR compared with WKY rats (WKY rats versus SHR, P<0.01) (Figure 1E).
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In DS rats, the most widely studied genetic model of salt-sensitive hypertension, supplemental dietary sodium increases blood pressure, but in the Dahl salt-resistant (DR) strain, supplemental dietary sodium has little effect on blood pressure.19 As shown in Figure 2A, the measurement of SBP of rats at 11 weeks of age showed that SBP of DS rats on a high-salt diet exceeded that of DS rats on a low-salt diet. CARP mRNA was more abundant in the H group than in the L group at 11 weeks of age (Figures 2B and 2C). SBP in the H group at 18 weeks, however, was comparable to that in the L group. Despite no significant difference in SBP at 18 weeks, the CARP mRNA level in the H group was significantly higher than that in the L group. Because of signs of congestive heart failure as demonstrated by cardiac dilatation and pleural effusion (data not shown), as well as a significant increase in left ventricular weight–to–body weight ratio at 18 weeks in the H group compared with that in the L group (>1.5-fold) (Figure 2D), an increased CARP expression may reflect not only elevated SBP but also cardiac hypertrophy and heart failure.
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CARP mRNA Levels Are Correlated With BNP mRNA Levels in Dahl
Rats
Because an increase in synthesis of BNP is closely associated with
left ventricular dysfunction,20 we compared
the BNP mRNA levels with CARP mRNA levels in the Dahl rat model that
appears to represent the transition from compensated heart
failure to decompensated heart failure. Data on CARP and BNP mRNA
levels were available from the same heart in 47 rats (7 rats at 6 weeks
of age, 12 rats at 11 weeks of age in the L group, 8 rats at 18 weeks
of age in the L group, 12 rats at 11 weeks of age in the H group, 8
rats at 18 weeks of age in the H group). As shown in Figure 2E, CARP mRNA levels are significantly correlated with each BNP mRNA
level.
Effects of p38 Mitogen-Activated Protein Kinase and Rac1
Activation on CARP and BNP Promoters
To determine the molecular mechanisms underlying the induction of
CARP mRNA levels in pressure-overloaded cardiac hypertrophy
and heart failure, we constructed the luciferase reporter plasmid
CARP-1832Luc, which consists of 1832 bp of the 5'-flanking
sequence and 170 bp of the 5'-untranslated region of the human CARP
gene. This construct was then transiently transfected into primary
cultures of neonatal rat cardiac myocytes along with p38 and the
constitutive active form of Rac1 (V12Rac1) expression plasmid.
Figure 3A shows that
cotransfection with p38 or V12Rac1 expression plasmids increased
luciferase activity driven from CARP promoter by 10.2- and 7.5-fold,
respectively. Because of the apparent coordinate regulation between
CARP and BNP mRNA levels, we assessed the effects of overexpression of
p38 or V12Rac1 on the BNP promoter activity. Results were similar to
that seen in CARP-1832Luc reporter gene; cotransfection of p38 or
V12Rac1 strongly activated the BNP-1000Luc reporter gene, which
contains sequence from -1000 to +70 of the rat BNP gene. Figure 3B shows that the ability of wild-type p38 expression vector to
induce luciferase activity derived from CARP promoter is significantly
attenuated in the presence of a specific inhibitor of p38,
SB203580. These results confirm our conclusion that p38
activates CARP promoter.
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M-CAT Box at -40 Mediates p38- and Rac1-Induced CARP
Expression
To determine the cis-regulatory elements responsible
for p38- or V12Rac1-induced CARP expression, a series of 5'-deletion
constructs was transfected. Although removal of sequence from -1832 to
-206 resulted in a 80% decline in basal reporter activity (data
not shown), the fold-induction of promoter activity derived from
CARP-206Luc in response to the expression of either p38 or V12Rac1 was
comparable to that seen with CARP-1832Luc (see later). A search of the
sequence downstream of -206 revealed the presence of a 5'-CATTCT-3',
or M-CAT, consensus sequence lying between -37 and -31 in the
complementary strand. We then determined whether the M-CAT box in the
CARP promoter could serve as a binding site for M-CAT box-binding
protein or proteins. The incubation of nuclear extracts from cardiac
myocytes with the radiolabeled double-stranded
oligonucleotide containing M-CAT box gave rise to
single protein-DNA complex (Figure 4A).
Binding affinity of the nuclear proteins to M-CAT element in CARP
promoter seems to be less pronounced than that to M-CAT element in the
BNP promoter because 5 ng (10-fold molar excess) unlabeled
BNP(-113/-95) completely competed for the binding to CARP(-42/-25),
whereas 5 ng (10-fold molar excess) unlabeled CARP(-42/-25) only
modestly competed for the binding to BNP(-113/-95) probe. As shown in
Figures 4B and 4C, the point mutations, which abolished the
interaction with M-CAT box-binding protein or proteins, resulted in a
significant reduction in the responsiveness to the expression of p38 or
V12Rac1. Thus, the M-CAT element in the CARP promoter is functionally
important for p38- or V12Rac1-inducible activity of the CARP
promoter.
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Discussion |
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Cardiac Hypertrophy and CARP
The findings in the present study have an important implication in the cardiac gene regulation in response to pressure overload for the following 2 reasons. First, in contrast to many hypertrophy-associated genes (eg, ANP, ß-MHC, skeletal
-actin),21 CARP expression is developmentally increased
in the hearts, thus indicating that the induced expression of the CARP
gene is not considered to be a reactivation of the fetal genetic
program. Second, CARP is a nuclear protein expressed most exclusively
in the heart,5 6 and an increase in CARP mRNA levels is
rapid and sustained during cardiac hypertrophy. Such an
expression profile displays a sharp contrast to the other
hypertrophy-inducible nuclear factors (c-fos,
c-jun, c-myc, and egr-1), which are
ubiquitously expressed and transiently increased in response to cardiac
overload.1 In this regard, an induced expression of
the CARP gene suggests the role in the regulation of cardiac gene
expression during ongoing cardiac hypertrophy. Indeed,
previous studies demonstrated that transient transfection of CARP
expression vector decreased many of the cardiac genes, including
cardiac -actin, skeletal -actin, and cardiac troponin C
genes.5
Correlation Between CARP and BNP Expression
It should be noted that despite comparable SBP between L and H
groups at 18 weeks of age, CARP expression was significantly elevated
in the H group. These findings raised the possibility that factors
other than the SBP can also contribute to the elevation of CARP mRNA
levels. It has been demonstrated that the expression of proinflammatory
cytokines such as interleukin-1ß, monocyte chemotactic and
activating factor, and monocyte chemoattractant protein-1 is increased
in the DS rat hearts at 18 weeks of age.22 These findings
led us to suggest that the augmented expression of CARP is in part
ascribed to the increase in expression of these cytokines.
Consistent with this hypothesis, we recently found that
interleukin-1ß increases CARP expression in vitro (data not
shown).
Previous studies suggested that BNP levels are closely associated with the impairment of systolic function.20 23 The correlation of CARP with BNP mRNA levels in the Dahl rat model suggests that these 2 genes are regulated by shared mechanisms. Alternatively, transcription of the BNP gene may be regulated by CARP. The latter possibility, however, seems to be unlikely because the overexpression of CARP has little effect on BNP promoter as assessed with transient transfection assays and because adenovirus-encoding CARP had no effects on BNP mRNA levels in cardiac myocytes (data not shown).
Activation of CARP Promoter by p38 Mitogen-Activated
Protein Kinase and Rac1 Through M-CAT Element
In an attempt to understand the mechanisms through which CARP
expression is increased by cardiac overload, we investigated the roles
of p38 and Rac1 in the CARP promoter activity because p38 and Rac1 have
been implicated in hypertrophy of ventricular
myocytes.24 25 Transcription factors such as c-Jun, ATF-2,
and Elk-1 have been shown to be the major substrates of
stress-responsive mitogen-activated protein (MAP) kinases,
including p38.26 27 It has been demonstrated that
phosphorylation of DNA binding domains by
stress-responsive MAP kinases enhances DNA binding activity and
activates transcriptional activity.28 However, the
physiological consequence of the activation of
stress-responsive MAP kinases largely remains
controversial.29 30 Nemoto et al31 indicated
that p38 mediates hypertrophic agonist-induced ANP promoter, whereas
JNK represses it. Our results with transient transfection and gel-shift
assays indicate that p38 and Rac1 induce CARP promoter in an M-CAT
element–dependent manner. M-CAT element has initially been described
as an element that confers the muscle specificity to the cardiac
troponin T gene.32 Subsequent studies have shown that the
M-CAT element is critically involved in the inducible expression of
several cardiac genes in response to protein kinase C or Ras
activation.33 34 35 In this regard, our data expand
understanding of the potential function of M-CAT element in mediation
of the response to p38- and Rac1-dependent signals. Because a major
form of M-CAT binding factor has been reported to be a transcription
enhancer factor-1 (TEF-1),36 although there are multiple
forms of the TEFs,37 it is intriguing to speculate that
the transcriptional activating function of TEF-1 is regulated by
phosphorylation via p38 MAP kinase cascade. Further
studies are necessary to examine this possibility.
Model of Regulation of Cardiac Hypertrophy by
CARP
Our observations suggest a model for CARP in the regulation of
cardiac hypertrophy (Figure 5). The roles of stress-activated
protein kinase (SAPK) in the development of the hypertrophic response
have been studied extensively but are still far from conclusive.
Previous studies to date have consistently demonstrated that
hypertrophic agonists, including phenylephrine and
endothelin-1, activate p38 in cardiac myocytes.24
However, the extent of the involvement of these pathways in the
regulation of hypertrophic response remains controversial. The results
of the present study implicated p38 in the transcriptional
activation of CARP gene as well as the BNP gene through M-CAT–binding
proteins. Because our recent experiments suggest that the
overexpression of CARP by adenovirus inhibits protein synthesis and
cellular enlargement, we assume that CARP exerts its
inhibitory effects on cardiac hypertrophy.
Taking into the consideration that ANP and BNP are highly inducible
during cardiac hypertrophy and act as antihypertrophic
peptides, the inducible expression of antihypertrophic protein CARP in
response to pressure overload may be considered a fundamental mechanism
that underlies the adaptation to cardiac overload.
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In summary, we found that CARP expression is regulated by cardiac overload, including pressure overload, hypertension, and heart failure. The findings that M-CAT element mediates the induction of CARP and BNP promoters in response to stress-responsive MAP kinases will add to our understanding of how cellular stresses regulate these 2 genes. To the best of our knowledge, this is the first report that implicates a myocardial tissue–restricted nuclear factor as a genetic marker for cardiac hypertrophy.
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Acknowledgments |
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This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sport and Culture of Japan and by a grant from the Japan Cardiovascular Foundation.
Received July 26, 1999; first decision September 7, 1999; accepted February 13, 2000.
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