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Christchurch Cardioendocrine Research Group, Department of Medicine, Christchurch School of Medicine, Christchurch 8001, New Zealand
Address all correspondence and requests for reprints to: Dr. Vicky A Cameron, Department of Medicine, Christchurch School of Medicine, P.O. Box 4345, Christchurch 8001, New Zealand. E-mail: vicky.cameron{at}chmeds.ac.nz
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Abstract |
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-smooth muscle actin, characteristic of the
transformation to myofibroblasts, and raised ANP concentrations in the
medium. In the surviving myocardium of the left ventricle, ANP and BNP
expression increased in response to ligation, BNP mRNA was particularly
strong at the lateral margins of the infarct. In both left and right
atria, levels of BNP mRNA increased markedly over the first 18 h,
whereas levels of atrial ANP mRNA decreased over 3 days after
infarction. This is the first report of ANP expression and synthesis by
cardiac fibroblasts invading the fibrotic scar, suggesting that ANP may
be involved in regulating fibroblast proliferation during reparative
fibrosis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Plasma levels of ANP and BNP are markedly elevated in heart failure (5) and after myocardial infarction (MI) (6), and are powerful predictors of ventricular dysfunction and mortality (7). Moreover, within heart tissue, gene expression of both ANP and BNP is reportedly up-regulated in animal models of MI and heart failure (8, 9, 10, 11) and in human heart disease (12, 13). Although ANP is expressed primarily in the atria in adults, the ventricle is the major site of both ANP and BNP expression in embryos (14). The appearance of increased ANP expression in adult ventricles is a marker for induction of the embryonic gene program during the development of hypertrophy (15).
Most previous studies of natriuretic peptide expression in cardiac tissues have used Northern blotting or ribonuclease protection assays, and information about the cellular localization of natriuretic peptide expression during the response to myocardial infarction is sparse. To understand the molecular mechanisms involved in the response to cardiac ischemia, it is necessary to determine which cell type expresses the gene of interest. The cellular response to cardiac injury is initiated by an invasion of inflammatory cells, followed by infiltration by endothelial cells and fibroblasts to form granulation tissue. A complex interplay of paracrine factors released by macrophages and injured myocytes triggers the phenotypic switch of fibroblasts to myofibroblasts (16), which deposit collagen to form the fibrotic scar. Changes at the site of injury are accompanied by ongoing hypertrophy and remodeling of the noninfarcted myocardium. The present study compares the cellular distribution of ANP and BNP expression at several time points corresponding to these stages of healing in infarcted and noninfarcted myocardium up to 5 weeks after left coronary artery ligation in sheep.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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44 kg BW) underwent left lateral
thoracotomy and coronary artery ligation. These sheep were killed
18 h, 3 days, 7 days (n = 3 at each time), 3 weeks (n =
2), and 5 weeks (n = 7) after ligation, and the hearts were
excised for tissue sampling. Four sham ligation control sheep underwent
thoracotomy without ligation and were killed at 5 weeks. In addition,
cardiac tissue was collected from the corresponding regions of three
sheep that had not undergone surgery to provide control data. General anesthesia was induced by thiopentone (17 mg/kg, iv) and was maintained with halothane and nitrous oxide, with continuous monitoring of electrocardiography and arterial pressure. Left lateral thoracotomy and ligation of the coronary artery were performed as described previously (17, 18). Postoperative analgesia was provided by 50 mg pethidine, im. This study was approved by the animal ethics committee of the Christchurch School of Medicine.
In situ hybridization, immunohistochemistry, and histology
After an overdose of sodium pentobarbitone (150 mg/kg),
the heart was excised, and the dimensions (square centimeters) of the
infarct were assessed by spreading the infarcted tissue flat over a
centimeter grid. Tissue samples were rapidly collected and fixed in 4%
paraformaldehyde with 0.1 M borate buffer (pH 9.5).
In situ hybridization was performed on 20-µm cryostat
sections, as described previously (19). The ovine ANP and
BNP RNA probes were generated by in vitro transcription from
DNA templates bearing 5'- and 3'-extensions encoding T7 and T3 RNA
polymerase promoter sequences. The ovine ANP complementary DNA
template, a 296-bp fragment of exon 2, was generated by PCR from sheep
genomic DNA using primers based on the published ovine sequence
(20) (ANP reverse primer, 5'-TTTGGAGGACAAGATGCCT; forward
primer, 5'-CCCAATCCACTCTGGGCT). The ovine BNP complementary DNA
template, a 240-bp fragment of exon 2, was also generated by PCR from
sheep genomic DNA (BNP reverse primer, 5'-AGCTGTTGGACCGTCTACGA; forward
primer, 5'-TTGCAGCCCAGGCCACTGA). Adjacent sections were hybridized with
ANP, BNP, and their respective control sense probes and exposed to
x-ray film for 48 h. Sections were dipped in NTB-2 nuclear track
emulsion (Eastman Kodak Co., Rochester, NY) for 14 days,
developed, and counterstained with hematoxylin and eosin.
Immunohistochemistry for the detection of ANP immunoreactivity (ANP-IR)
was performed on paraffin-embedded tissues using a peroxidase-labeled
streptavidin-biotin kit (DAKO Corp., Carpinteria, CA). The
antiserum against ovine ANP (21) was used at a final
dilution of 1:500. Control sections were processed identically, except
that the ANP antiserum was preabsorbed with 0.1 mg/ml human ANP
(Peninsula Laboratories, Inc., Belmont, CA). Additional
controls were performed in which the ANP antibody was omitted to check
for endogenous tissue peroxidase. Adjacent infarct sections were also
stained for collagen using Masson Trichrome and were immunostained for
factor VIII (to identify endothelial cells), -smooth muscle actin
(SMA) and vimentin (to identify myofibroblasts), using
peroxidase-labeled streptavidin-biotin kits (DAKO Corp.).
Culture of ovine cardiac fibroblasts
Ovine cardiac fibroblasts were grown in primary culture
following the method of Hafizi et al. (22).
Briefly, tissue blocks were excised from the infarct and periinfarct
region of sheep heart 1 week after left coronary artery ligation and
placed into HBSS with 20 mmol/liter HEPES at 4 C. The tissue was minced
in HBSS using two sterile scalpels, transferred to HBSS with 1000 U/ml
collagenase II (270 U/mg; Life Technologies, Inc.,
Gaithersburg, MD), and placed in a shaking water bath (37 C) for 2
h. To ensure cell dispersion, the mix was passed through a 50-ml
syringe several times and reincubated for an additional hour. The cells
were washed with fibroblast growth medium, consisting of DMEM
(Life Technologies, Inc.) supplemented with 2 mmol/liter
L-glutamine, 100 U/ml penicillin, 100 µg/ml
streptomycin, and 10% FCS (Life Technologies, Inc.);
centrifuged (5 min at 1200 rpm); resuspended in fibroblast growth
medium, and plated onto 10-cm plates. At 5 days the cells were
trypsinized and replated onto six-well plates at equivalent density.
Forty-eight hours later, the culture medium was replaced, and
triplicate wells were treated with either 10 ng/ml transforming growth
factor-ß (TGFß; R and D Systems, Minneapolis, MN) or
control medium. To prevent endopeptidase degradation of ANP,
phosphoramidon (2 x
10-5
M; Sigma, St Louis, MO) was added to
all wells. After a further 48 h, the medium was removed for ANP
assay (21). The cell density was calculated by counting
nuclei in 10 individual microscope fields. Additional cultures were
grown under identical conditions in microscope slide chambers and
immunostained for SMA, as described above.
Densitometry and statistics
The intensities of the ANP and BNP signals were quantified by
measuring the densities of the x-ray autoradiographs. Imaging and data
capture were performed on a Gel Doc 2000 (Bio-Rad Laboratories, Inc., Richmond, CA), and the densities were assessed within a
representative area, using the Quantity One software package.
Nonparametric statistical analyses were performed on the density data.
Kruskall-Wallis analysis was used to compare the grouped data for each
cardiac region to determine whether a significant response to
myocardial infarction was obtained, and the Mann-Whitney U test was
applied to determine at which time points the response was
significantly different from control. Concentrations of ANP in the cell
culture experiments were analyzed by ANOVA. Significance was taken at
the P < 0.05 level.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression within the infarct and periinfarct regions
Gene expression of ANP and BNP in samples collected from the
region of the infarct (thin-walled area with no surviving myocardium)
and from the periinfarct area (transition between ischemic tissue and
viable myocardium) are shown in Fig. 1
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Natriuretic peptide expression in tissues from control sheep and
sham-operated sheep were comparable, and only tissues from the control
sheep are illustrated. The apex of the left ventricle of control sheep
displayed very low levels of ANP and BNP messenger RNA (mRNA), with
scattered foci of positive cells. At 18 h and 3 days after
ligation, the infarcted region consisted entirely of enuclated
myocytes, and no expression of either ANP or BNP within infarcted
tissue was detected. However, at 7 days, when degradation of the
necrotic myocardium and infiltration by fibroblasts were observed, ANP
mRNA became apparent on both epicardial and endocardial aspects of the
infarct, but was more marked on the endocardial side. Expression of ANP
in the infarct was still pronounced at 3 weeks after ligation, but was
barely detectable at 5 weeks. In contrast, BNP expression was not
detectable in the infarct at any time. Both ANP and BNP sense probes
were run in parallel in all experiments and gave similarly low levels
of background hybridization. In the interests of space only the BNP
sense autoradiographs are illustrated in Figs. 1 and 4. Periinfarct
samples were collected from the lateral margins of the infarct (Fig. 1), which included zones of dead myocardium that lacked expression of
either natriuretic peptide and zones of viable myocardium exhibiting
intense expression of both ANP and BNP. The intensity of BNP expression
was particularly strong in these periinfarct regions at 18 h and 3
days after ligation; this was the only site of sampling in which BNP
expression exceeded that of ANP.
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, A and B), indicated
by the clustering of silver grains over the fibrotic scar.
Identification of ANP-IR in fibroblasts was confirmed by staining with
Masson Trichrome, which detects collagen deposition, characteristic of
fibrosis (Fig. 2C). Levels of background can be seen in control
sections hybridized with an ANP sense probe (Fig. 2D). The synthesis of
ANP peptide by fibroblasts was established by immunocytochemistry (Fig. 2E), which showed a cellular distribution of ANP-IR similar to that of
ANP mRNA in 7-day, 3-week, and 5-week tissue sections. Control sections
incubated with ANP antiserum preabsorbed with excess ANP or with
primary antibody omitted showed no staining (Fig. 2F). The ANP-IR was
observed in bands of fibroblasts, especially in regions adjacent to the
necrotic myocardium. In contrast, hybridization with a BNP probe showed
no detectable signal within fibrotic tissue (Fig. 2G). The cellular
localization and timing of ANP staining at 7 days were coincident with
the appearance of SMA (Fig. 2H) and vimentin (not shown), indicative
of the phenotypic switch of fibroblasts to myofibroblasts. The
distribution of ANP staining was distinct from that of endothelial
cells, identified by immunostaining for factor VIII, which stained
endothelial cells lining blood vessels and in columns migrating into
the scar (not shown).
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SMA immunostaining. In contrast, cardiac fibroblasts treated with
TGFß for 48 h stopped proliferating, so cell density was
significantly lower (36 ± 15 cell/field) than that in control
cells (436 ± 88 cells/field; P < 0.001).
Fibroblasts treated with TGFß stained intensely for SMA
microfilaments (not shown), characteristic of the transformation to
myofibroblasts. The ANP concentrations in medium collected from the
wells treated with TGFß (2.86 ± 0.09 pmol/liter) were slightly,
but significantly, greater than those in wells treated with either
medium alone (2.23 ± 0.09 pmol/liter; P = 0.008)
or medium from control cells (2.43 ± 0.22 pmol/liter;
P = 0.05).
Expression in noninfarcted myocardium
Samples were taken from the left and right atria, mid
left ventricle (1 cm from the edge of the infarct), remote left
ventricle (above the point of attachment of the papillary muscles), mid
right ventricle, and mid interventricular septum. The mean densities of
ANP and BNP expression in each cardiac chamber are summarized in Fig. 3, comparing ligated sheep with control
sheep. The densities of ANP and BNP mRNA in ventricular samples are
corrected for levels of background hybridization (the densities
obtained with their respective sense probes subtracted), because the
nonspecific hybridization tended to increase after ligation in the
ventricular tissues.
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and 4). In contrast, there was a significant
increase in atrial BNP expression in the group data after ligation. The
most marked increase in both left and right atrial BNP mRNA was over
the first 18 h after ligation, showing an average 2-fold increase
in response to ligation. Despite this marked activation of BNP mRNA in
response to ligation, absolute levels of BNP expression in the atria
remained less than those of ANP in both control and ligated sheep.
Levels of ANP and BNP expression also increased significantly in
samples of mid left ventricle (distinct from the infarcted region) and
remote left ventricular myocardium over the first 3 days after ligation
(Fig. 3). Levels of BNP mRNA in mid left ventricle were significantly
greater than control values at 18 h after ligation. Levels of ANP
and BNP expression in right ventricle and interventricular septum
tended to increase after ligation, but were not significantly different
from control values after correcting for background. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression of ANP by cardiac fibroblasts has not previously been reported to our knowledge. However, a role for ANP in the proliferation of fibroblasts of cardiac origin has been suggested by a number of reports. First, cardiac fibroblasts express all three NP receptors (23) and can generate the second messenger cGMP in response to both ANP and CNP. Second, ANP inhibits the DNA synthesis and proliferation of cardiac fibroblasts in culture (24, 25), and ANP inhibits the synthesis of collagen by rat and human cardiac fibroblasts via cGMP (26). Previously, it has been assumed that any action of ANP on fibroblasts is paracrine, after production by adjacent myocardial cells. Transcription of the ANP gene in nonmyocyte cells is normally repressed through the binding of fibroblast nuclear extracts to an E box motif and adjacent sequences within the ANP promoter (27). It is feasible that the phenotypic switch of fibroblasts to myofibroblasts may allow induction of the ANP promoter in these cells.
In vivo, the appearance of myofibroblasts has been linked to
a complex interplay of locally produced growth factors, including
angiotensin II, endothelin-1 TGFß, and platelet-derived growth factor
(16). However, it has been reported that cultured skin
fibroblasts can be induced to transform to myofibroblasts by treatment
with TGFß alone (28). To determine whether cardiac
fibroblasts could also be induced to transform to myofibroblasts in
culture, cardiac fibroblasts were cultured from sheep heart 1 week
after myocardial infarction in the current study. Cardiac fibroblasts
treated with TGFß also displayed intense SMA immunostaining and a
decrease in cell density, indicating the phenotypic switch of these
cells to myofibroblasts. Associated with TGFß treatment was a small,
but significant, increase in ANP concentrations in the culture medium
compared with those in control fibroblasts despite the fact that the
cell density of TGFß-treated cultures was 10-fold lower than that of
control fibroblasts. These ANP levels are very low, and in
vivo other growth factors may elicit a greater release of ANP.
However, if ANP acts in an autocrine manner within the fibrotic region,
small changes in ANP levels may be sufficient to activate receptors on
adjacent cells.
There is now considerable in vitro data suggesting that ANP may have a role in regulating the proliferation of fibroblasts and the resultant deposition of collagen. A role for ANP in regulating the development of fibrosis in vivo is supported by the observation of cardiac fibrosis in knockout mice, which lack the gene for the natriuretic peptide receptor A (29). These mice have hypertension, which is lethal in males by 6 months of age, and exhibit both ventricular hypertrophy and fibrosis. This model suggests that ANP may play a major role in regulating ventricular remodeling secondary to compensatory hypertrophy and cardiac fibrosis. These studies lead us to suggest that ANP may be involved in an autocrine manner in regulating fibroblast proliferation during reparative fibrosis. At present, we do not know whether ANP is also expressed in reactive fibrosis in ventricles during mechanical overload. Chronic models of hypertrophy and fibrosis could clarify whether fibroblasts responsible for reactive fibrosis show ANP expression. One report describing a transgenic mouse model of hypertropic cardiomyopathy (30) observed numerous foci of ANP expression in the ventricles in regions associated with fibrosis and collagen accumulation.
Several neuroendocrine factors involved in cardiac fibroblast proliferation could be involved in triggering the expression of ANP in fibroblasts 7 days after infarction. Angiotensin II secreted from adjacent myocardium and macrophages is reported to induce hypertrophy and fibrosis by releasing TGFß1 and endothelin-1 from fibroblasts (31) and stimulating the expression of the transcription factors Egr-1 and c-Fos in cultured cardiac fibroblasts (32). Both TGFß1 and basic fibroblast growth factor, which are involved in the growth of cardiac fibroblasts and the switch to myofibroblasts during fibrosis (16), have been demonstrated to stimulate ANP secretion from cultured neonatal cardiomyocytes (33). In this study, TGFß1 alone elicited a rise in ANP levels in cardiac fibroblast cultures, but the role of basic fibroblast growth factor in ANP production by cardiac fibroblasts was not examined.
In contrast to ANP, we did not detect BNP expression in infarcted myocardium. Synthesis of BNP is regulated in part by modulating BNP message stability through downstream cis-acting sites on the BNP mRNA (34). It is possible that BNP is transiently expressed in the fibrotic scar, but we failed to detect it. Like ANP, BNP and CNP also have been implicated in the regulation of fibroblast mitogenesis (24, 25). Levels of CNP expression in myocardial tissue are considered to be extremely low (35), and hence, expression of CNP was not examined in this study. However, CNP also strongly inhibits DNA synthesis in cultured cardiac fibroblasts (25), and the natriuretic peptide receptor B is expressed in fibroblasts (23). To date, there have been no reports of CNP synthesis by fibroblasts, but CNP may also participate in the regulation of fibroblast proliferation.
This study is the first to compare the concurrent changes in ANP and BNP expression at the cellular level in all cardiac chambers over several weeks following MI. Cardiac expression of ANP and BNP mRNA over 3 days after infarction has been compared in rats using Northern blotting (8, 11). In those studies a rapid rise of BNP mRNA was observed in both atria and ventricles, as early as 4 h after coronary artery ligation (8), and a later increase in ANP mRNA (3 days) was observed in ventricles. Although previous studies in rats have consistently observed increased ANP mRNA in ventricles after MI, atrial ANP mRNA has been reported to be decreased (36), unchanged (11, 37, 38), or increased (39).
These previous studies are consistent with the present study of the response of ANP and BNP after infarction. We observed atrial ANP expression to decrease over the first 3 days after MI, whereas there was a rapid increase in atrial BNP expression within 18 h. The left ventricle showed marked increases in both ANP and BNP mRNA, especially at the margins of the infarct, which may be a response to both the regional mechanical stress as well as hemodynamic overload (40). The changes in mRNA observed in this study also correlate well to circulating levels of ANP and BNP in response to MI in sheep. After coronary artery ligation, the relative increase in plasma BNP in response to MI was greater than that in ANP (17). Despite this, the absolute levels of plasma ANP exceeded BNP both at baseline and after MI, concordant with the relationship between cardiac expression of ANP and BNP reported here.
Previous studies of ANP or BNP synthesis at the cellular level after myocardial infarction have generally examined the infarcted ventricle only. Increased ANP-IR was seen at the lateral margins of the infarct in rat hearts after coronary artery ligation (8, 41). Similarly, intense BNP-IR was observed in myocytes surrounding the infarct (8). Hama and co-workers observed no ANP-IR or BNP-IR in infiltrating cells or fibrous tissue sampled up to 3 days after MI. This finding is not at odds with the present study, in which ANP-IR in fibroblasts was not observed until 7 days after MI. One previous study examined ANP mRNA in the rat heart after coronary artery ligation (36) by in situ hybridization and observed ANP expression in the ventricular epicardium bordering the infarct area 1 week post-MI. The identity of the cells producing ANP was not established.
In conclusion, this study has documented the regional changes in ANP and BNP gene expression in heart tissue up to 5 weeks after coronary artery ligation in an ovine model of myocardial infarction. The results have established that BNP mRNA responds more rapidly and with a greater relative rise than ANP mRNA, particularly in the atria. Expression of both peptides was markedly increased in the left ventricle, especially at the margins of the infarct. The present study also describes ANP expression and synthesis by cardiac fibroblasts within the fibrotic scar, coinciding with the transition of these cells to myofibroblasts. This finding leads to the proposal that ANP is involved in an autocrine manner in regulation of fibroblast proliferation and possibly the phenotypic switch to myofibroblasts during reparative fibrosis.
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Acknowledgments |
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Footnotes |
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Received April 18, 2000.
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References |
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-smooth muscle
actin expression in granulation tissue myofibroblasts and in quiescent
and growing cultured fibroblasts. J Cell Biol 122:103–111-actin transcription on cardiac
muscle by two fibroblast growth factors. Proc Natl Acad Sci USA 87:7066–7077-adrenergic
receptor activation: potential roles for protein kinase C and
mitogen-activated protein kinase. Mol Endocrinol 10:1719–1727This article has been cited by other articles:
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