Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202
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ABSTRACT |
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Brain
natriuretic peptide (BNP) gene expression and chronic activation of the
sympathetic nervous system are characteristics of the development of
heart failure. We studied the role of the -adrenergic signaling
pathway in regulation of the human BNP (hBNP) promoter. An hBNP
promoter (
1818 to +100) coupled to a luciferase reporter gene
was transferred into neonatal cardiac myocytes, and luciferase activity
was measured as an index of promoter activity. Isoproterenol (ISO),
forskolin, and cAMP stimulated the promoter, and the
2-antagonist ICI 118,551 abrogated the effect of ISO. In
contrast, the protein kinase A (PKA) inhibitor H-89 failed to block the
action of cAMP and ISO. Pertussis toxin (PT), which inactivates
G
i, inhibited ISO- and cAMP-stimulated hBNP promoter
activity. The Src tyrosine kinase inhibitor PP1 and a dominant-negative
mutant of the small G protein Rac also abolished the effect of ISO and
cAMP. Finally, we studied the involvement of M-CAT-like binding sites
in basal and inducible regulation of the hBNP promoter. Mutation of
these elements decreased basal and cAMP-induced activity. These data
suggest that
-adrenergic regulation of hBNP is PKA independent,
involves a G
i-activated pathway, and targets regulatory
elements in the proximal BNP promoter.
cardiomyocytes; gene regulation; adrenergic signaling; M-CAT elements; protein kinase A
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INTRODUCTION |
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BRAIN NATRIURETIC PEPTIDE (BNP), originally isolated from porcine brains, is constitutively expressed in the adult heart and is primarily a ventricular hormone, in contrast to atrial natriuretic peptide, which is highly expressed in adult atria (8). BNP has vasodilator, natriuretic, and diuretic properties. BNP gene expression is induced in the infarcted heart and elevated during the development of heart failure (26), and circulating plasma BNP is a marker of left ventricular dysfunction in these pathophysiological states (3, 27, 35).
Adrenergic signaling pathways, mediated by both 1- and
-adrenoreceptors (
- or
-AR), regulate gene expression and
growth of cardiac myocytes (reviewed in Refs. 9, 15, 37). When activated by norepinephrine binding,
1-ARs couple to the
G protein G
q, resulting in activation of
serine/threonine kinases, such as protein kinase C (PKC) (reviewed in
Ref. 32) and p42/44 mitogen-activated protein kinase (MAPK) (9, 15).
The
1-AR agonist phenylephrine (PE) has been shown to
increase rat BNP mRNA (13) as well as activate the rat BNP promoter
(34).
The -AR couples primarily to G
s proteins, resulting
in activation of adenylyl cyclase, elevation of intracellular cAMP, and
activation of protein kinase A (PKA) (9). Chronic activation of the
sympathetic nervous system occurs during the development of heart
failure, resulting in major alterations in
-adrenergic signaling.
Both decreased
1 receptors and increased
G
i protein content contribute to these changes (9).
Moreover,
-ARs can also couple to pertussis toxin-sensitive
G
i protein in cardiac myocytes (36). Cross-coupling of
-AR to G
i has been studied extensively in COS-7 and
HEK-293 cells, and results indicate that the
-subunit of
Gi activates the nonreceptor tyrosine kinase Src, resulting
in Ras-dependent activation of p42/44 MAPK (1, 6, 7, 23, 24). Such
alterations in
-AR signaling also play a role in the increased
protein synthesis that accompanies hypertrophic growth of cardiac
myocytes. Recent studies indicate that activation of
-ARs with
either norepinephrine (38) or the
-agonist isoproterenol (ISO) (40)
stimulates protein synthesis in neonatal ventricular myocytes (NVM).
Moreover, ISO-induced protein synthesis involves PKA as well as
coupling of the receptor to G
i, the tyrosine kinase Src,
the small G protein Ras, and p42/44 MAPK (40). To our knowledge, no one
has addressed whether a similar mechanism is involved in
-adrenergic
regulation of cardiac-specific gene expression. Because BNP is a marker
gene for cardiac hypertrophy, infarction, and heart failure, we
hypothesized that its regulation by a
-AR agonist would involve a
similar mechanism.
In our studies, we used transient transfection of the human BNP (hBNP)
promoter coupled to a luciferase reporter gene to determine the
signaling pathways by which ISO and cAMP regulate the hBNP promoter. In
addition, we mutated putative regulatory elements in the proximal hBNP
promoter to test their involvement in -adrenergic regulation. Our
data indicate that ISO and cAMP activate the hBNP promoter and that
proximal regulatory elements are involved in this response. Moreover,
the effect of ISO and cAMP is mediated by G
i, the
tyrosine kinase Src, and the small G protein Rac.
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MATERIALS AND METHODS |
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Cell culture. Ventricular myocyte-enriched cultures were generated from Sprague-Dawley rat pups (Charles River, Kalamazoo, MI) as described previously (21). Myocytes were separated from myocardial fibroblasts by differential plating. NVM were plated for 40 h in DMEM (GIBCO) containing 100 U/ml penicillin, 100 µg/ml streptomycin, 2 mM glutamine, 10% fetal bovine serum (HyClone), and 0.1 mM 5'-bromo-2'-deoxyuridine to inhibit proliferation of contaminating fibroblasts. Cultures were maintained under serum-free conditions, with DMEM supplemented with 5 mg/l insulin and transferrin and 2.5 mg/l selenium. After 24 h under serum-free conditions, cells were treated with the appropriate agent for 24 h and then lysed for assay of luciferase and protein. Inhibitors were added for 1 h before treatment with ISO or cAMP. The dosage was based on a survey of the literature and preliminary studies. All studies were approved by the Henry Ford Hospital Committee for the Care of Experimental Animals and were performed in accord with the National Research Council Guide for the Care and Use of Laboratory Animals.
Northern blot. BNP mRNA was detected by Northern blot, as described previously (20). RNA was measured by laser scanning densitometry. BNP mRNA was normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA for quantitation of the multiples of increase vs. untreated controls.
Plasmid constructions and mutagenesis.
Chimeric hBNP-luciferase reporter gene constructs have been described
previously (21). PCR was used to generate mutations in the hBNP
proximal promoter. Oligonucleotides included restriction sites at their
5' and 3' borders to facilitate subcloning (Hind III on the sense primer and BamH I on the antisense primer are not included in the following sequences). Putative regulatory elements
were identified on the basis of sequence comparison with consensus
elements. The muscle cardiac traponin T (M-CAT)-like element at
position 124 is referred to in the text as 124BNP and the
element at
97 as 97BNP. Whereas the 124BNP element extends from
124 to
118 on the sense strand
(5'-CATTCCC-3'), the 97BNP element extends from
91
to
97 on the antisense strand (5'-CATTCCG-3'). The
activating protein (AP)-1-like element at position
111 has an additional base pair (T at
108) vs. the
consensus element (5'-TGAC/GTCA-3') and is referred to as
111BNP. Mutated 124BNP (M124) has three bp changes
(5'-GGTACCC-3'). Mutated 97BNP (M97) has three bp
changes (5'-CTTAGTG-3').
Transfection and luciferase assay. Transfection was performed, and luciferase activity was assayed as described previously (21). Briefly, freshly isolated ventricular myocytes were transiently transfected in PBS-glucose by electroporation at 280 V and 250 µF with a Bio-Rad gene pulser. For the hBNPLuc constructs, 1 µg was transfected per 3 × 106 cells. In cotransfection experiments, 10 µg of the dominant-negative mutant of Ras, Raf, or Rac were used. After transfection, the cells were aliquoted into 3 wells of a 12-well plate and, 40 h later, the medium was changed to serum-free DMEM. After 24 h in serum-free medium, cells were treated with the appropriate agents for 24 h and then harvested, lysed, and assayed for luciferase activity (Luciferase Assay System, Promega) with an OptoComp 1 luminometer (MGM) according to the manufacturer's protocol. Duplicate aliquots of cell lysate from triplicate wells were assayed and averaged. Luciferase activity was normalized to protein levels, as described previously (21). At least two separate preparations of each plasmid were used for each experimental group. Data were expressed as means ± SE and were analyzed by one-way ANOVA, with multiple pairwise comparisons made by the Student-Newman-Keuls method. P < 0.05 was considered significant.
Nuclear extract.
Crude nuclear extracts were prepared from cultured NVM (6 × 106 cells per 15-cm tissue culture dish) maintained as
described for the transfection studies. Cells were washed in PBS,
scraped into PBS, and pelleted. Cells were lysed in buffer A
[10 mM HEPES (pH 7.9), 1.5 mM MgCl2, 10 mM KCl, 0.3 M
sucrose, 1 mM dithiothreitol (DTT), 0.5% NP-40, 1 mM
phenylmethylsulfonyl fluoride (PMSF), and 1 µg/ml each of antipain,
chymostatin, pepstatin, and leupeptin]. The nuclei were pelleted
and protein was extracted in buffer B [10 mM HEPES (pH
7.9), 25% glycerol, 0.42 M NaCl, 1.5 mM MgCl2, 0.2 mM
EDTA, 1 mM PMSF, 1 mM DTT, and 1 µg/ml each of antipain, chymostatin,
leupeptin, and pepstatin]. Protein concentration was measured
using Coomassie reagent, with BSA as the standard (Pierce). Nuclear
protein was diluted to 5 mg/ml, aliquoted, and stored at
70°C.
Electrophoretic mobility shift assay.
To detect binding of nuclear protein to putative cognate binding sites,
we used the electrophoretic mobility shift assay (EMSA; Gel Shift Assay
System, Promega). Oligonucleotides were synthesized, and their
complementary strands were annealed before their use as probe or
competitor. An 0.0175-pmol 5' end-labeled double-stranded oligonucleotide was used as a probe. Binding reactions were carried out
in buffer containing 50 mM NaCl, 1 mM MgCl2, 0.5 mM EDTA, 0.5 mM DTT, 4% glycerol, 10 mM Tris · HCl (pH 7.5),
0.05 mg/ml poly (dI-dC), and 5-10 µg of cardiomyocyte nuclear
protein. Unlabeled oligonucleotides (1.75 pmol) used as competitors of
binding were preincubated with nuclear protein before the labeled probe
was added. DNA-protein complexes were separated out on a 4%
nondenaturing acrylamide gel in 0.5× TBE buffer. After
electrophoresis, the gel was dried and exposed to film for 1-3
days. The sequences of the oligonucleotides used in EMSA are as follows
(regulatory elements printed in boldface): 1)
131/
113 hBNP (124BNP) (21): 5'-AGGGGCTCATTCCCGGGCC-3'; 2)
M-CAT (cardiac troponin T) (10): 5'-CGTGTTGCATTCC
TCTCTG-3'; 3) GT-IIC (SV40 enhancer) (31):
5'-CCAGCTGTGGAATGTGTGT-3'; i4)
101/
88 hBNP (97BNP) (21):
5'-GGCCCGGAATGTGG-3'; 5) Myc-Max
(E-box): 5'-AAGCAGACCACGTGGTCTGCTTCC-3'.
Chemicals.
Endothelin (ET)-1 was obtained from Peninsula (San Carlos, CA),
dibutyryl cAMP, +/-isoproterenol dihydrochloride, phenylephrine, propranolol, metoprolol, and ICI 118,551 from Sigma (St. Louis, MO),
and forskolin and H-89 from Biomol (Plymouth Meeting, PA). The Myc-Max
oligonucleotide containing the consensus E-box element was purchased
from Santa Cruz Biotechnology (Santa Cruz, CA), and the Sp1
oligonucleotide was obtained from Promega. All other routine chemicals
and supplies were obtained from Fisher and Sigma.
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RESULTS |
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Effect of ISO and cAMP on BNP mRNA and the hBNP promoter.
To test whether -adrenergic signaling regulates BNP mRNA in rat NVM,
myocytes were treated with either 100 µM ISO or a stable form of
cAMP, dibutyryl cAMP (dbcA, 1 mM). Northern blots showed that ISO and
dbcA stimulated BNP mRNA 3.6 ± 0.5-fold and 3.8 ± 1.5-fold, respectively (Fig. 1).
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Effect of the Gi inhibitor PT and the
Src tyrosine kinase inhibitor PP1 on regulation of the hBNP promoter.
We next tested whether the signaling mechanism for ISO- and
cAMP-stimulated hBNP promoter activity involves cross-coupling to
G
i. When myocytes were treated with 500 ng/ml pertussis
toxin (PT), which inactivates G
i, ISO- and
cAMP-stimulated hBNP promoter activity was decreased by 40 and 76%,
respectively (Fig. 3A). This effect
was specific to G
i-activated pathways, as PT had no
effect on IL activation of the hBNP promoter and little effect on PE
activation (data not shown). The fact that PT failed to completely
inhibit ISO-stimulated hBNP promoter activity may be due to several
factors: 1) 100 µM ISO activates both
1- and
2-ARs, and stimulation of both might have some
antagonistic effects; 2) although there are more
1-ARs on cardiac myocytes, only
2-ARs couple to G
i; 3)
2-ARs
preferentially activate the hBNP promoter, and because they are less
abundant than
1-ARs, they may be preferentially downregulated by 24 h of treatment with ISO.
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Effect of dominant-negative small G proteins on regulation of the
hBNP promoter.
Studies indicate that -AR stimulation of Src results in activation
of the Ras-Raf-MEK-p42/44 MAPK pathway (23, 24, 38). We tested whether
overexpression of a dominant-negative mutation of the small G protein
Ras (dnRas) would inhibit ISO and cAMP stimulation of hBNP promoter
activity but found that it had no effect (data not shown). In addition,
a dominant-negative form of Raf also had no effect. These
dominant-negative signaling molecules effectively inhibit regulation of
the hBNP promoter in cardiac myocytes; indeed, we found that dnRas
inhibits IL stimulation of the hBNP promoter (14), and dnRaf inhibits
ET-1 activation of the hBNP promoter (He and LaPointe, unpublished data).
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Role of M-CAT-like elements in basal and cAMP-inducible expression
of the hBNP promoter.
We have shown that the proximal region of the hBNP promoter (127
to
40) is highly active in ventricular myocytes (21). Putative
regulatory elements in this region include two M-CAT-like elements
(124BNP and 97BNP). Many cardiac muscle-specific genes are regulated by
M-CAT elements (17, 25, 31, 33, 34). To see whether 124BNP and 97BNP
are important for basal regulation of the hBNP promoter in ventricular
myocytes, they were mutated individually in
1818hBNP. Mutation
of 124BNP and 97BNP resulted in a 60 and 96% decrease in luciferase
activity, respectively (Fig. 5).
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DISCUSSION |
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We explored the signaling mechanisms by which the -AR agonist ISO
and cAMP activate the hBNP promoter. Our data show that 1) ISO
stimulation of the hBNP promoter is mediated primarily by
2-ARs; 2) ISO and cAMP activate the hBNP
promoter through G
i-, Src-, and Rac-dependent pathways;
3) the effect of ISO and cAMP on promoter activity does not
appear to involve PKA; and 4) ISO and cAMP target 97BNP, which
is an M-CAT-like element.
Both 1- and
1-adrenergic signaling
pathways induce hypertrophy of cardiac myocytes, including increased
protein synthesis, upregulation of early response genes, and fetal gene
expression (e.g., the natriuretic peptide genes) (4, 5, 9, 15). Our
results indicate that ISO and cAMP regulation of the hBNP promoter has
both similar and distinct properties compared with
-AR signaling in
nonmyocyte cell lines (1, 6, 7, 23, 24) and
-AR regulation of
protein synthesis in myocytes (40). The similarities include the
involvement of G
i and the tyrosine kinase Src. The major
differences are that, in our studies, 1) the small G protein
Rac seems to be a major effector, rather than Ras, and 2) the
effect of ISO and cAMP seems to be independent of PKA.
In the nonmyocyte cell lines, cAMP couples the -adrenoreceptor to
activation of Ras. Thus an important question derived from our data is
how ISO and cAMP couple to Rac. We know of no studies showing that
either
-AR signaling or cAMP directly activates Rac; however,
Kawasaki et al. (18) identified a cAMP-binding protein that can
activate the small G protein Rap1 independently of PKA. Thus cAMP may
regulate a factor that controls Rac activation. On the basis of studies
of
2-AR overexpression (1, 6, 7, 23, 24), it is also
possible that cAMP acts directly or indirectly to activate Src kinase,
which in turn activates Rac. Of interest, both Src and Rac have been
implicated in the pathway leading to cardiac myocyte hypertrophy in
vitro (22, 29). Although Rac normally activates the stress pathways
c-Jun kinase (JNK) and p38 MAPK, such mechanisms may not be involved in
ISO and cAMP regulation of the hBNP promoter, as dominant-negative
inhibitors of both pathways had no effect (unpublished data). In
addition, we have previously shown that the cytokine IL activates the
hBNP promoter in a Rac- and p38 MAPK-dependent fashion, but neither p42/44 nor JNK seems to be involved (14). Because hypertrophy, ischemic
injury, and heart failure are characterized by production of
inflammatory cytokines and catecholamines and upregulation of the BNP
gene, the small G protein Rac could well be an important transducer of
multiple receptor-mediated signaling pathways activated during these
pathophysiological events.
As mentioned above, our data also suggest that ISO and cAMP activation
of the hBNP promoter is independent of PKA. The PKA inhibitor H-89 is
very specific, with an inhibitor constant or Ki of 0.048 µM for PKA vs. 32 µM for PKC. In
these studies, we used low doses (0.1 and 1 µM), which had no effect
on ISO and cAMP stimulation of hBNP promoter activity. In contrast, 10 µM of H-89 inhibited other factors, including IL and PE, suggesting nonspecific effects. Whether 2-AR responses in cardiac
myocytes are dependent on cAMP and PKA has been debated. Studies
suggest that the inotropic effect of
2-AR is dissociated
from cAMP/PKA signaling (2). However, more recently it has become
apparent that
2-AR responses depend on very localized
increases in cAMP and affect sarcolemmal L-type Ca2+
channels but not cytoplasmic contractile regulatory proteins (19, 39).
In fact, the components of cAMP signaling, including G proteins,
adenylyl cyclase, and PKA regulatory subunits, are colocalized to
caveolae (specialized plasma membrane vesicles) in many types of cells
(30). Thus it is possible that our studies with H-89 failed to show a
response because the inhibitor was unable to target the proper PKA
isoform. Another possibility is that activation of the
2-AR produces intracellular signals in addition to cAMP,
as Pavoine et al. (28) have recently shown. In their studies,
2-AR activation was coupled to the release of
arachidonic acid by the cytosolic isoform of phospholipase A2 (cPLA2). Additional studies are needed to
determine whether
2-AR regulation of the hBNP promoter
is dependent on additional intracellular signals, such as arachidonic
acid and its metabolites.
Our study also indicates that basal and cAMP-inducible regulation of the hBNP promoter targets cis elements in the proximal promoter. We identified two M-CAT-like elements in the proximal promoter of the hBNP gene, 97BNP and 124BNP, by sequence homology to consensus elements. Mutation of these elements within 1818 bp of the hBNP 5' flanking sequence indicated that each contributes to basal expression, but disruption of 97BNP almost completely eliminates promoter activity, whereas disruption of 124BNP has only a partial effect. Another difference is that 97BNP was able to bind M-CAT binding factors (MCBF or TEF), as determined by competition with unlabeled M-CAT and GT-IIC consensus oligonucleotides; in contrast, 124BNP was only able to compete for binding at high concentrations. On the basis of comparison with two noncompetitive binding sites (E-box and Sp1), it is unlikely that 124BNP is an M-CAT element.
cAMP regulation of the hBNP promoter involves both 97BNP and 124BNP,
neither of which is associated with an E-box element, distinguishing
the hBNP promoter from -myosin heavy chain (
-MHC) (12). Just as
with basal regulation of the promoter, cAMP-inducible regulation is
more dependent on 97BNP than on 124BNP. PKA and the CRE/AP-1-like
element in the proximal hBNP promoter do not mediate the effect of
cAMP. Because dnRac inhibits cAMP stimulation of the hBNP promoter, it
is most likely that a Rac-dependent signaling molecule is involved in
regulating the activity of a factor(s) binding to 97BNP. 97BNP seems to
be an important target for other signaling pathways, as previous
studies from our laboratory have shown it to be targeted by both IL
signaling and p38 MAPK (14). Additional studies are needed to determine
whether a particular kinase signaling pathway mediates the effect of
Rac, or whether other Rac-mediated signals, such as reactive oxygen
species, are involved in regulation of the hBNP promoter.
M-CAT elements are also important in -adrenergic inducible
regulation of cardiac-specific genes (16, 17, 33, 34). However, our
data indicate that neither PE nor ET targets the 97BNP M-CAT-like
element, in contrast to studies on the rat BNP promoter, which indicate
that PE targets the M-CAT element via PKC- and Ras-dependent mechanisms
(34). Although both rat and human BNP genes contain M-CAT and GATA
elements in their proximal promoters, the elements are not arranged in
the same fashion. The proximal rat BNP promoter contains one M-CAT
element upstream from two GATA elements, whereas the hBNP promoter
contains one M-CAT-like element, one GATA element, and one AP-1-like
element (21). Thus functional differences in regulation of the two
genes may be the result of interactions between proteins binding to M-CAT sites and adjacent cis elements. In support of this
concept, we found that mutation of the GATA element at
85 in the
hBNP promoter resulted in a 70% decrease in cAMP-stimulated promoter activity (He and LaPointe, unpublished observations), suggesting that
multiple interactions are required for cAMP's effect.
In summary, our studies indicate that ISO and cAMP regulate the hBNP
promoter through a pathway utilizing Gi, Src, and Rac, targeting an M-CAT-like element in the proximal hBNP promoter. In
addition, a second regulatory element, 124BNP, contributes in part to
basal and cAMP-inducible regulation of promoter activity. Coupled with
our previous data indicating that the cytokine IL upregulates the hBNP
promoter in part by targeting the 97BNP M-CAT-like element (14), it
would appear that multiple signaling pathways are focused on modulating
the activity of regulatory factors that interact with this region of
the hBNP promoter. Because cytokines are induced and
-adrenergic
signaling is altered in the failing heart, studies on regulation of the
hBNP gene may provide insights into the molecular mechanisms underlying
a number of pathophysiological conditions, such as hypertrophy,
ischemic injury, and heart failure.
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ACKNOWLEDGEMENTS |
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We thank Fangfei Wang for excellent technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-03188 and HL-28982 (to M. C. LaPointe).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202-2689 (E-mail: mclapointe{at}aol.com).
Received 3 August 1999; accepted in final form 12 January 2000.
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