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(Circulation. 2000;102:1315.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Monocyte Chemoattractant Protein-1 is Upregulated in Rats With Volume-Overload Congestive Heart Failure
From Cardiovascular Pharmacology, SmithKline Beecham, King of Prussia, Pa (T.M.B., N.A., R.W.C., X.L., P.K., E.O., J.W.); Department of Cardiology, Klinikum Innenstadt, LMU, Munich, Germany (T.M.B., C.E.A.); Cardiovascular Research, DuPont, Wilmington, Del (X.W., G.Z.F.); and Faculty of Medicine, Technion, Haifa, Israel (J.W.).
Correspondence to Thomas M. Behr, MD, Department of Cardiovascular Pharmacology, UW2510, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, King of Prussia, PA 19406. E-mail thomas_m_behr{at}sbphrd.com
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Chemokines are potent proinflammatory and immune modulators. Increased expression of chemokines, eg, monocyte chemoattractant protein-1 (MCP-1), has recently been described in clinical and experimental heart failure. The present report is aimed at exploring the expression, localization, and binding site regulation of MCP-1, a member of the C-C chemokine family, in a rat model of volume-overload congestive heart failure (CHF).
Methods and Results—An aortocaval fistula was surgically created between the abdominal aorta and inferior vena cava. Rats with CHF were further subdivided into compensated and decompensated subgroups. Northern blot analysis and real-time quantitative polymerase chain reaction demonstrated upregulation of MCP-1 mRNA expression correlating with the severity of CHF (288±22, 502±62, and 826±138 copies/ng total RNA for sham, compensated, and decompensated animals, respectively; n=5, P<0.05). MCP-1 protein was localized by immunohistochemistry in cardiomyocytes, vascular endothelium and smooth muscle cells, infiltrating leukocytes, and interstitial fibroblasts, and its intensity increased with severity of CHF. In addition, rats with CHF displayed a significant decrease of 125I-labeled MCP-1 binding sites to myocardium-derived membranes (384.3±57.0, 181.3±8.8, and 123.3±14.1 fmol/mg protein for sham, compensated, and decompensated animals, respectively).
Conclusions—Volume-overload CHF in rats is associated with alterations in the expression, immunohistochemical localization, and receptor binding of the MCP-1 chemokine in the myocardium. These changes were more pronounced in rats with decompensated CHF. The data suggest that activation of the MCP-1 system may contribute to the progressive cardiac decompensation and development of CHF in rats with aortocaval fistula.
Key Words: cardiomyopathy • immunohistochemistry • molecular biology • receptors
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Proinflammatory cytokines have been implicated in clinical deterioration in congestive heart failure (CHF) since an increase in plasma as well as myocardial levels of the cytokine tumor necrosis factor (TNF)-
was found in patients with advanced
heart failure due to ischemic or idiopathic
cardiomyopathies.1 2 3 4 TNF- and
other proinflammatory cytokines, such as interleukin (IL)-1ß
and IL-6 or interferon-
are also known to induce several chemotactic
polypeptides known as chemokines.5 6 The locally acting
chemokines, which have the primary function of inducing chemotaxis,
constitute a family of >40 known polypeptides, classified into
subfamilies on the basis of the relative position of their cysteine
residues.7
Serological studies have shown upregulation of certain chemokines in
human CHF.8 In particular, monocyte chemoattractant
protein (MCP)-1 is a C-C chemokine produced in a variety of cells in
response to injury or exposure to other cytokines, such as
IL-1, IL-6, TNF-, or interferon-.6 9 The information
about MCP-1 involvement in experimental heart failure is scant and
incomplete. Transgenic overexpression of MCP-1 in the
myocardium resulted in myocarditis and subsequent
development of heart failure.10 Pressure overload–induced
heart failure in hypertensive animals led to induction of
MCP-1.11 To date, the contribution of MCP-1 to the
syndrome of heart failure is attributed solely to its potent
chemoattractant properties on monocytes, the presence of which has been
documented in cardiac specimens of heart failure. Interestingly,
angiotensin II (Ang II), which plays a dominant role in the
pathogenesis of CHF, also induces MCP-1 gene expression in vivo and in
vitro.12 13
Rats with aortocaval fistula (ACF) develop volume-overload–induced cardiomyopathy characterized by marked cardiac dilatation and hypertrophy and subsequently CHF.14 15 16 This experimental model of CHF is characterized by renal, hemodynamic, and neurohormonal alterations that closely mimic the changes observed in patients with severe heart failure.14 15 16 17 Furthermore, rats with ACF can be subdivided, on the basis of their daily urinary sodium excretion, into compensated and decompensated subgroups, which differ in the degree of severity of CHF.15 Thus, in addition to renal retention of sodium and water, rats with decompensated CHF display a marked degree of neurohormonal activation compared with the compensated subgroup.14 15
Therefore, in the present study, we characterized the changes in the expression of MCP-1 mRNA and protein in rats with compensated and decompensated heart failure, using a novel real-time polymerase chain reaction (PCR) technique18 combined with standard Northern blotting and immunohistochemistry. In addition, because no data are available on MCP-1 receptors in the myocardium in CHF, binding assays were performed to confirm the presence of and characterize the alterations in MCP-1 receptor in this experimental model of heart failure.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Studies were performed on male Wistar rats weighing
300 g.
Animals were kept in temperature- and light-controlled rooms. Tap water
and standard rat chow were provided ad libitum. Experiments were
conducted in accordance with the Guide for the Care and Use of
Laboratory Animals (US Department of Health, NIH publication
85-23).
Experimental Model
An abdominal ACF was surgically created according to the method
of Stumpe et al.19 Briefly, rats were anesthetized
with pentobarbital sodium (40 mg/kg). The vena cava and aorta were
exposed via a midline abdominal incision. A side-to-side (1.0- to
1.2-mm) anastomosis was created distal to the origin of the renal
arteries. Rats were allowed to recover and placed in individual
metabolic cages for daily monitoring of urine output and
electrolyte excretion. Sham-operated animals served as controls. Rats
with ACF were divided into 2 subgroups according to their daily
excretion of sodium (UNaV) on postoperative day 5 and later, ie, rats
with decompensated CHF (UNaV <200 µmol/d) and rats with
compensated CHF (UNaV >1400 µmol/d). The urine was
analyzed for UNaV with a Beckman Synchron AS8 clinical
analyzer. Systolic blood pressure was measured by a
noninvasive tail-cuff method with an IITC Life Science Apollo
Analyzer, model 179BP. For tissue collection, rats were
anesthetized with pentobarbital sodium 24 hours, 3 days, and 7
days after surgery. Their hearts were removed, immediately frozen in
liquid nitrogen, and stored at -80°C.
Echocardiography
Animals were anesthetized with isoflurane (1% to
1.5%). Echocardiographic images were obtained with an
ATL HDI5000CV ultrasound unit with an L12-5 linear array transducer. 2D
guided M-mode recordings of the left ventricle in the
short-axis view at the level of the papillary muscles were obtained,
and left ventricular dimensions and wall thicknesses
were measured.
RNA Extraction
Total RNA was extracted from cardiac tissue from both ventricles
as described by Chomczynski and Sacchi20 after
homogenization in a commercial solution (Trizol,
Gibco) and quantified by spectrophotometry at 260/280 nm.
Northern Blot Analysis
Standard Northern blotting was used to investigate the time
course of MCP-1 expression as described in detail
previously.21 Total RNA (25 µg) was size-fractionated by
electrophoresis on 1.0% agarose gels and transferred onto a GeneScreen
Plus membrane (DuPont–New England Nuclear). Ribosomal protein L32
(rpL32) was used as a housekeeping gene.21 Primers were
designed according to published sequences (Table 1
). Probes were obtained by PCR,
gel-purified, labeled with [-32P]dATP (3000
Ci/mmol; Amersham Corp) by a random-priming DNA labeling kit
(Boehringer Mannheim), and hybridized at 42°C overnight.
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TaqMan Real-Time Reverse Transcription–PCR Analysis
The principle of real-time PCR detection is based on the
fluorogenic 5' nuclease assay.18 The TaqMan probes were
labeled with a 5' reporter dye, 6-carboxyfluorescein, and a
3' quencher dye, 6-carboxyltetramethyl-rhodamine. During the PCR
reaction, the AmpliTaq Gold DNA polymerase cleaves the TaqMan probe at
the 5' end and separates the reporter dye from the quencher dye only if
the probe hybridizes to the target. This cleavage results in the
fluorescent signal generated by the cleaved reporter dye and is
directly monitored by the ABI Prism 7700 Detection System
(Perkin-Elmer). The increase in the fluorescence signal is
proportional to the amount of specific PCR
product.18
The PCR primers and TaqMan probes were designed with a software program
from Perkin-Elmer (Table 1
). Specificity test, reverse
transcription, and PCR were carried out as described.22
Absolute copy numbers of the target transcripts per nanogram of
transcribed total RNA were determined with cloned plasmid DNA for rpL32
and MCP-1 as described earlier.22 The MCP-1 clone was
generated by use of the PCR product of the TaqMan sense primer and
the Northern antisense primer (Table 1). Data were
analyzed with a Sequence Detector V1.6 program
(Perkin-Elmer).
Immunohistochemistry
Frozen sections (6 µm thick) were cut and air dried for 1
hour. Sections were fixed in acetone for 10 minutes at -20°C and
blocked with 1% FBS (Sigma Chemical Co). Antibodies against rat MCP-1
(Santa Cruz), factor VIII (Sigma), and ED-1 (macrophage marker;
Sigma) were applied for 1 hour, appropriately diluted. After a wash in
PBS and incubation with peroxidase-conjugated secondary antibody for 45
minutes followed by another wash in PBS, sections were developed in
diaminobenzidine substrate (Vector), counterstained with hematoxylin,
and coverslipped with Cytoseal (Stephens Scientific). As control, 1
hour preincubations of MCP-1 antibody and peptide (Santa Cruz) and
experiments omitting the primary antibody were done.
MCP-1 Binding Studies
Membranes were prepared from frozen heart tissues isolated by
differential centrifugation from 3 rats from each group
(control, compensated, and decompensated CHF). Briefly, tissues were
homogenized in 10 volumes of ice-cold buffer containing
10 mmol/L Tris-HCl (pH 7.4), 5 mmol/L EDTA, 0.1 mmol/L
PMSF, 0.1 mg/mL of bacitracin, and 0.1 mmol/L aprotinin. The
homogenates were centrifuged at 1000g
for 10 minutes at 4°C, and the pellets were discarded. The
supernatants were centrifuged at 37 000g for 20
minutes at 4°C, the membrane pellets were washed twice, and the
protein content was finally adjusted to 2 mg/mL in incubation buffer
containing 20 mmol/L Tris-HCl (pH 7.4) and 5 mmol/L
MgCl2. The protein concentration was measured by
the Pierce bicinchoninic acid method with BSA (Pierce) as the
standard.
Radioligand binding assays were performed in triplicate and
repeated once with individual membrane preparations in the incubation
buffer. The membranes (25 µg) were incubated with a single
concentration of 125I-labeled MCP-1 (60 pmol)
(Amersham) with or without various concentrations of unlabeled human
MCP-1 (0.1 pmol to 100 nmol/L) for 60 minutes at 30°C. The
incubations were terminated by addition of 2 mL cold wash buffer (0.9%
NaCl) followed by rapid filtration over Skatron Filtermates presoaked
in 0.2% polyethyleneimine using a Skatron cell harvester (Skatron
Instruments).
The competition curves were analyzed by nonlinear regression with the Prism program (Graph PAD Software).
Statistical Analysis
Statistical comparisons were made by ANOVA followed by Tukey’s
multiple comparison test with the Graph PAD Prism program. Comparison
of 2 groups was made by unpaired Student’s t test. Values
of P<0.05 were considered statistically significant. Data
are presented as mean±SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Characterization of the Experimental Model
Table 2
presents selected
cardiovascular and renal parameters of
control and experimental groups. Rats with decompensated CHF were
characterized by a significantly lower UNaV, bradycardia, and a lower
systolic blood pressure compared with either compensated or
control animals. Also, the heart-to-body weight ratio was significantly
higher in rats with decompensated CHF. Similar findings have been
reported previously.15
Echocardiography demonstrated that decompensated
CHF was associated with a marked degree of cardiac dilatation (Table
2).
|
MCP-1 Expression: Northern Blot Analysis
Figure 1 presents the data on
the expression of MCP-1 and rpL32 mRNA, by Northern hybridization, in
control and ACF animals at 24 hours, 3 days, and 7 days, respectively.
The data on day 7 in the ACF animals are further subdivided into
compensated and decompensated CHF. An increased expression of MCP-1 was
observed from day 1 in ACF animals compared with sham-operated animals.
MCP-1 mRNA in decompensated animals was significantly higher than in
sham-operated animals at day 7 (P<0.05).
|
MCP-1 Expression: Real-Time PCR Analysis
For a more accurate quantification of mRNA levels, we
performed the sensitive TaqMan real-time PCR. Figure 2 shows a representative
study for MCP-1. MCP-1 plasmid was serially diluted, and real-time PCR
data were plotted with template copy numbers versus threshold cycle
(Ct) values (Figure 2A) or cycle numbers versus 
Rn (ratio of
reporter dye emission to quencher dye emission; Figure 2B). The
amplification (as indicated by the Ct value) was in a linear
relationship with the initial template concentration, and all testing
samples were located within range (Figure 2A).
|
The quantitative data (day 7) for MCP-1, normalized to the housekeeping
rpL32 transcript, are shown in Figure 3.
The levels of MCP-1 for sham-operated animals (n=5) were 288±22
copies/ng total RNA and increased to 665±90 in animals with ACF (n=10;
P<0.001) (Figure 3A). The separate analyses
for compensated and decompensated animals (Figure 3B) showed
502±62 copies/ng in compensated animals (n=5) and 826±138 copies/ng
in decompensated animals (n=5) (P<0.05 compared with
compensated and sham).
|
P<0.05 for decompensated vs compensated
animals.
Immunohistochemistry
Control experiments did not produce MCP-1 staining. The
immunoreactive staining for MCP-1 in sham, day 1, and day 3 ACF animals
was barely detectable. In contrast, in day 7 compensated and
decompensated animals, MCP-1 immunoreactivity was clearly increased. It
was expressed in endothelial cells and vascular smooth
muscle of blood vessels, as confirmed by serial staining with factor
VIII. Infiltrating cells accounted for only a small fraction of
MCP-1–positive interstitial cells, the majority being
capillary endothelium and presumably fibroblasts
(Figure 4). Macrophage staining
was quantified by counting 5 high-power fields (x200). There was a
significantly higher macrophage count in decompensated
(5.3±1.1) than in compensated (1.9±0.7) or sham animals (1.7±0.7) at
day 7 (P<0.05). Strikingly, MCP-1 immunoreactivity was
noted in cardiomyocytes of rats with decompensated CHF
(Figure 5) but not in
cardiomyocytes of control or compensated animals.
|
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Binding Assays
To further assess the significance of the alterations in the MCP-1
system in rats with experimental CHF, binding assays using human
recombinant 125I-labeled MCP-1 were carried out.
Although human MCP-1 differs from rat MCP-1 in the absence of 25 to 48
carboxy-terminal amino acids, the data clearly demonstrated
radioligand binding to the rat heart in a specific manner,
in the range of 70% to 80% of the total binding. Competition studies
demonstrated a single, high-affinity binding site. Homologous
competitive binding data were used to calculate the affinity of
recombinant human MCP-1 to the rat myocardium, yielding
IC50 values of 0.071±0.015, 0.28±0.06, and
0.14±0.04 nmol/L for sham, compensated, and decompensated animals,
respectively (P<0.05) (Figure 6A). The calculated values of the density
of binding sites were 384.3±57.0, 181.3±8.8, and 123.3±14.1 fmol/mg
protein for sham-operated, compensated, and decompensated animals,
respectively (P<0.05, compensated and decompensated CHF
versus sham; Figure 6B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we have demonstrated that volume-overload cardiomyopathy in rats with ACF is associated with an upregulation of the MCP-1 system in proportion to the severity of the disease. MCP-1 was expressed in a variety of cell types, including the adult cardiomyocyte. Moreover, our data demonstrate a saturable, specific binding site for MCP-1 in the rat myocardium that is downregulated in animals with experimental heart failure. We show that the expression of this chemokine was enhanced for an extended duration, rather than transiently, during the development of volume-overload cardiomyopathy. Furthermore, the overexpression of MCP-1 occurred primarily in animals with the decompensated form of the disease. Taken together, these findings suggest that MCP-1 might contribute to the pathogenesis of the myocardial changes in rats with experimental heart failure and perhaps to the evolution into a decompensated state. Although our study does not prove a direct linkage between activation of the MCP-1 system and the deterioration into a decompensated state of CHF, it is interesting to note that such an association has been suggested previously for other proinflammatory cytokines, in particular TNF-
.3 The induction
of an inflammatory response in the failing myocardium by
agents like MCP-1 or TNF- may lead to further deterioration in
cardiac performance and a consequent transition from a
compensated into a decompensated state. The demonstration of MCP-1 upregulation in the present study is based on several methodological approaches. In addition to Northern hybridization, we used a novel, quantitative real-time PCR technique based on the 5' nuclease activity of the Taq DNA polymerase. The real-time PCR uses the number of cycles needed to reach a fixed threshold amount of PCR product as a measure of the initial concentration of the target nucleic acid.18 22 The sensitive fluorescence detection system allows the Ct to be observed when PCR amplification is still in the exponential phase, thus avoiding the possibility that reaction components become limiting. The modification of using a cloned plasmid DNA template to obtain a standard curve in addition to a housekeeping gene, as done in these experiments, permits the measurement of the absolute copy numbers of the transcript, allowing the detection and quantification of low abundant target molecules with high accuracy.22
The notion that the MCP-1 system is upregulated in rats with ACF is
further supported by the immunohistochemical data. MCP-1
immunoreactivity was localized in endothelial cells,
smooth muscle cells, interstitial cells, and infiltrating
cells in the myocardium of rats with compensated and
decompensated CHF. Strikingly, in decompensated animals, MCP-1 protein
was also localized in cardiomyocytes. Previously, it was
shown that MCP-1 expression may occur in stimulated neonatal
cardiomyocytes in vitro.23 24 Although we
cannot exclude the possibility that MCP-1 was adsorbed to the cell
surface, the findings of our study suggest that the adult rat
cardiomyocyte is capable of expressing MCP-1 in vivo in
response to volume overload. Although this is reminiscent of the
TNF- expression in cardiomyocytes of the failing
myocardium,3 nothing is known at present
about the functional significance of this finding. MCP-1 may serve to
guide mononuclear cells to these cardiomyocytes to
phagocytize them; conversely, MCP-1 may have more direct effects on the
cardiomyocyte, as shown for induction of intercellular
adhesion molecule-1 by MCP-1.23 An earlier report on MCP-1
expression in a hypertensive model of heart failure in the rat reported
that MCP-1 expression was confined primarily to
endothelial cells and infiltrating
cells.11 The discrepancy with our results may be due to
the underlying cause of cardiomyopathy in the 2
different models.
The overall infiltration of macrophages in decompensated animals was significantly higher than in compensated and sham-operated animals. MCP-1 may play a role in the chemoattraction of these monocytes in accordance with the proposed main function of MCP-1 in heart failure, ie, its action on chemotaxis of monocytes, macrophages, and T lymphocytes.11 24 25 26
The mechanism responsible for the upregulation of MCP-1 in rats with
ACF has not been delineated in the present study. Because TNF-
has been shown to induce MCP-1 expression in other
systems,6 9 the possibility that TNF- could contribute
to the increase in MCP-1 in our model warrants further study. In
addition, this experimental model is characterized by a marked
activation of the systemic and intracardiac
renin-angiotensin system in proportion to the severity of
the disease.14 15 Indeed, an association between Ang II
and induction of MCP-1 gene expression has been documented in rat
vascular smooth muscle cells, in aortic tissues of hypertensive rats,
and in rat mesangial cells in experimental
nephritis.12 13 27 In vascular smooth muscle cells, the
Ang II–induced MCP-1 mRNA accumulation was mediated by the
AT1 receptor.12 Further studies are
necessary to test the possibility that such a relationship between Ang
II and MCP-1 also exists in the myocardium of rats with
ACF.
In addition to overexpression of MCP-1 in the myocardium,
our data also suggest that volume-overload CHF in rats is associated
with decreased myocardial binding of the chemokine. At present, no
data are available on MCP-1 binding properties in cardiac tissues.
Human MCP-1 binds predominantly to the chemokine receptor
CCR-2.28 Although human and rat MCP-1 proteins share only
a 55% identity, human MCP-1 exerts biological effects in the
rat.23 Thus, it was possible to determine the presence of
an MCP-1 binding site by use of iodinized human MCP-1 as a ligand. Our
data show that with the development of severe heart failure, the MCP-1
binding site was downregulated like other binding sites, such as the
ß-adrenergic receptor or the TNF- receptor.3 The
mechanism by which the MCP-1 receptor is regulated in our model of
heart failure warrants further investigation. The possibility that the
receptors were saturated with endogenous MCP-1, which may
not be completely washed out during the membrane preparation, cannot be
ruled out. However, additional mechanisms have been implicated in the
downregulation of the MCP-1 receptor in other systems. In addition to
lipopolysaccharides and other microbial agents,29
TNF-, IL-1, and interferon- caused a rapid and drastic reduction
of CCR-2 mRNA and protein levels in vitro.30 31 Thus,
cytokines that upregulate MCP-1 may lead to downregulation of
MCP-1 receptor and thus modulate the recruitment of monocytes and
possibly other actions of MCP-1.
In summary, the findings of the present study indicate that volume-overload CHF in rats with ACF is associated with upregulation of the myocardial MCP-1 system in proportion to the severity of the disease, as well as with downregulation in MCP-1 binding sites. It is suggested that these changes may contribute to myocardial dysfunction and the progression of CHF in rats with ACF.
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Acknowledgments |
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The authors are grateful to Joyce Mao for the preparation of the oligonucleotide primers and to Dr Zaid Abassi for his valuable support.
Received February 24, 2000; revision received April 10, 2000; accepted April 13, 2000.
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