© 2000 American Heart Association, Inc.
UltraRapid Communication |
Reduced Myocardial Nerve Growth Factor Expression in Human and Experimental Heart Failure
From the Baker Medical Research Institute, Melbourne, Australia.
Correspondence to Dr David Kaye, Molecular Neurocardiology Laboratory, Baker Medical Research Institute, PO Box 6492, StKilda Rd Central, Melbourne VIC 8008, Australia. E-mail david.kaye{at}baker.edu.au
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Abstract |
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Abstract—Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained. Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (n=11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (n=11, P<0.05). In a rat model of CHF, a 40% reduction (P<0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content (P<0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 µmol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. The full text of this article is available at http://www.circresaha.org.
Key Words: heart failure • nerve growth factor • sympathetic nervous system
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Introduction |
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The clinical features and adverse prognosis associated with congestive heart failure (CHF) represent the result of a complex interplay between impaired cardiac performance and neurohormonal activation. Sympathetic nervous system excitation has been well documented to exist in CHF, based on measurements of plasma catecholamines,1 radiotracer isotope dilution determination of norepinephrine (NE) spillover rates to plasma,2 and measurement of multiunit postganglionic muscle sympathetic nerve discharge rates.3 Coupled with these data, recent observational and clinical trial data highlight the adverse effect of prolonged sympathetic overactivity in CHF patients.4 5 6 7
In addition to the documentation of a systemic increase in sympathetic tone in CHF, neurochemical studies of the rate of regional NE spillover indicate considerable regional heterogeneity in the pattern of sympathetic activation, this typically occurring earliest and being most elevated in the myocardium.2 8 Although the rate of NE spillover from cardiac sympathetic neurons to plasma is dependent on the nerve firing rate,9 other factors including the neuronal reuptake rate and innervation anatomy are of importance. Within this context, the paradoxical observation of reduced sympathetic nervous innervation density in the failing heart despite increased catecholamine overflow remains unexplained.10
Nerve growth factor (NGF) is the prototypic member of a family of proteins termed neurotrophins that play a pivotal role in the differentiation, maturation, and survival of innervating neurons.11 12 Specifically, in the periphery, NGF plays an important role in the maintenance and survival of both sympathetic and sensory neurons.13 Although it has been previously shown that the heart expresses NGF,14 15 the specific cellular source or its regulation has not been closely examined.
Given the critical role of the cardiac sympathetic nervous system in the pathophysiology of CHF, and the evidence for an apparent reduction in innervation density, we therefore aimed to characterize the expression of NGF in human and experimental cardiac failure. In addition, we aimed to identify whether cardiomyocytes express NGF and to investigate potentially relevant mechanisms for regulating expression of the neurotrophin.
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Materials and Methods |
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Human Heart Failure and Transcardiac NGF Flux
Simultaneous arterial and coronary sinus blood sampling was performed in 11 healthy volunteers and 11 patients with severe CHF (mean age: 44±7 versus 54±3 years, P=NS), as previously described.4 The mean left ventricular ejection fraction for the CHF group was 17±2%, and the average New York Heart Association heart failure class was 3.1±0.1. The cause of heart failure was nonischemic in 7 patients and ischemic in 4 patients. All patients received angiotensin-converting enzyme (ACE) inhibitors, diuretics, and digoxin, and 1 patient received a ß-blocker. The study was conducted with the approval of the Alfred Hospital Ethics Committee. Plasma NGF concentrations were determined by ELISA (Boehringer-Mannheim). All samples were assayed in triplicate.
Coronary Artery Ligation Model of Heart Failure
Heart failure was induced in Sprague-Dawley rats (210 to
300 g) by coronary ligation, as described by Pfeffer et
al.16 The study was conducted with the approval of the
Baker Medical Research Institute Animal Ethics Committee. Eight weeks
later, hemodynamic assessment of heart failure severity
was performed, followed by excision of the heart. Left
ventricular samples were obtained for subsequent reverse
transcription–polymerase chain reaction (RT-PCR), tissue NGF content
(by immunoassay; Boehringer-Mannheim), or
catecholamine fluorescence.
Myocardial Catecholamine Fluorescence
Histofluorescence specific for
catecholamines was performed using the sucrose-potassium
phosphate-glyoxylic acid method as previously described.10
This technique is a sensitive, well-developed method for studying
sympathetic innervation.17 Sections were photographed at
x200 magnification using 35-mm film, under UV fluorescence.
The number of stained catecholamine profiles was counted in
5 separate noninfarcted zones, and the result was averaged.
Cardiomyocyte Cell Culture
Neonatal rat ventricular myocytes were isolated from
D1-3 Sprague-Dawley rats, as previously described.18
Myocytes were plated on plastic culture dishes at a density of 1000
cells/mm2.
RNA Isolation and Semiquantitative RT-PCR
Total cellular RNA was isolated as described.19
Based on known sequences, primers were synthesized for NGF, the NGF
receptor trkA, and the housekeeping gene L7.20 21 22 RNA
(400 ng) was reverse-transcribed according to the manufacturer’s
instructions (MuLV; Perkin-Elmer). Amplification of the resultant cDNA
for NGF and L7 was performed by PCR (27 cycles; 94°C for 30 seconds,
63°C for 30 seconds, and 72°C for 1 minute) in a reaction that
included 0.04 µCi/µL 32P dCTP. TrkA PCR
amplification was performed over 35 cycles. PCR reaction products
were electrophoresed on a 5% polyacrylamide gel and
analyzed by phosphorimaging.
Western Blotting
Protein extracts were prepared from myocyte cultures collected
in a radioimmunoprecipitation assay lysis buffer. Extracts (50 µg)
were subjected to electrophoretic separation through a 10%
SDS-polyacrylamide gel and subsequently transferred to
nitrocellulose. Equal protein loading was confirmed by staining with
Coomassie blue (see Figure 1
online; http://www.circresaha.org).
Western blot analysis was performed by incubating the membranes
with an anti–NGF monoclonal antibody (Santa Cruz), followed by a
HRP-conjugated goat anti-rabbit antibody (1:5000). Membranes were then
exposed to a chemiluminescent reagent (Renaissance; NEN) and
autoradiographed using Kodak XOMat AR film.
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Statistical Analysis
Data are presented as mean±SEM. Between-group
comparisons were performed by unpaired Student’s t test.
Non–normally distributed data were compared by Mann-Whitney
U test. A P value <0.05 was considered
statistically significant.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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NGF Release by the Human Heart
To determine whether the human heart released NGF and to examine the influence of heart failure on this phenomenon, we performed simultaneous arterial and coronary sinus blood sampling for the determination of the regional transcardiac NGF plasma concentration gradient. Both the arterial and coronary sinus plasma NGF concentrations were substantially greater in healthy control subjects than CHF patients (Figure 1
).
Furthermore, the transcardiac NGF concentration gradient
was substantial and significantly higher than in CHF patients (221±134
versus 1.6±9.4 ng/mL, P<0.05), as shown in Figure 1.
NGF Expression in Experimental Heart Failure
Eight weeks after the induction of heart failure by
coronary artery ligation, typical markers of
hemodynamic compromise were demonstrated by
hemodynamic evaluation (Table). Rats were only selected
if the myocardial infarct was of at least moderate size, defined as an
infarct involving at least 20% of the left ventricular
circumference by planimetry (data not shown). Increases in left
ventricular end-diastolic pressure, left
ventricular weight, and lung weight were noted as cardinal
features of CHF (Table). After the induction of heart failure,
there was a 40% reduction (P<0.05) in the myocardial
expression of NGF mRNA as determined by semiquantitative RT-PCR. In
parallel, NGF protein expression was significantly lower in myocardial
tissue from rats with CHF (control versus CHF: 11.2±0.7 versus
8.4±0.8 pg/mg P<0.05).
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Indices of Myocardial Sympathetic Innervation
To investigate whether loss of sympathetic neurons from the
myocardium was apparent in our experimental model of CHF,
we used two complementary approaches. Histological
assessment (see Figure 2 online; http://www.circresaha.org) of
fluorescence staining for catecholamines revealed a
substantial reduction in the failing, noninfarcted
myocardium (Figure 2A), and,
in association, mRNA expression of the sympathetic neuronal NGF
receptor trkA was largely undetectable in the failing heart compared
with sham animals (Figure 2B).
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NGF Expression and Regulation in Cardiomyocytes
To address the potential mechanism for the observed changes in NGF
expression in heart failure, we studied the role of sympathetic tone
per se, acting via NE, as a regulator of NGF expression in
cardiomyocytes. NGF mRNA was readily detected in isolated
neonatal rat ventricular cardiomyocytes, as
assessed by RT-PCR using species-specific primers as described below.
Sequencing of the PCR amplification product confirmed the identity
of the product, with 100% homology at the predicted amino acid
sequence level (data not shown). In subsequent experiments aimed at
studying the regulation of NGF mRNA, we used a semiquantitative RT-PCR
approach. To ensure that the PCR reaction had not reached a plateau
phase of amplification, we examined the relationship between the number
of amplification cycles and product generation. With 400 ng of
total RNA, the amplification of both NGF and the housekeeping gene L7
was linear over the range of 21 to 29 cycles (data not shown), and,
accordingly, 27 cycles of amplification were selected for both
genes.
Exposure of neonatal cardiomyocytes to 10 µmol NE
resulted in a consistent reduction in NGF mRNA to 56±9%
(P<0.01) of that observed in control cells (Figure 3A). This effect on NGF mRNA expression
was also confirmed by Northern blot analysis (see Figure 3
online; http://www. circresaha.org). The action of NE was largely
abolished by the 
-adrenoceptor antagonist prazosin,
whereas the ß-adrenoceptor antagonist
propranolol was without effect. Furthermore, the role of
protein kinase C (PKC) in mediating the actions of NE on NGF expression
was examined using the PKC inhibitor bisindolylmaleimide.
Consistent with the apparent role of -adrenoceptors in the
regulation of NGF mRNA, exposure to 100 nmol/L bisindolylmaleimide also
abolished the NGF mRNA downregulation elicited by 10 µmol/L NE
(Figure 3A). In parallel studies, we also examined the influence
of NE on NGF protein expression in neonatal cardiomyocytes.
As with NGF mRNA expression, NE downregulated NGF protein levels, as
assessed by Western blot analysis, and this effect was also
blunted by prazosin (Figure 3B).
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Discussion |
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The sympathetic nervous system plays a vital role in the regulation of myocardial performance, contributing to the maintenance of cardiovascular homeostasis under both acute and chronic challenges to circulatory stability. Target-organ responses to sympathetic nervous stimulation are directly related to the intrasynaptic concentration of the relevant neurotransmitter, NE. The local synaptic NE concentration is tightly controlled in both a spatial and temporal sense by a number of factors, including the innervation neuroanatomy, nerve discharge rate, catecholamine synthesis, and reuptake rate. Although the mechanisms for regulating some of these processes are well understood, factors that regulate innervation neuroanatomy are less clear. NGF is the best-characterized member of a family of closely related peptide neurotrophic factors that contribute to the development and maintenance of sympathetic innervation.
Under certain clinical circumstances, most notably chronic CHF, activation of the sympathetic nervous system plays a key role in the pathophysiology of the disease process.5 6 7 Our group and others have identified the degree of cardiac sympathetic activation as being a highly relevant factor in determining outcome for CHF patients.4 23 24 Despite data indicating augmented release of NE from the failing heart, histological examination of the failing heart indicates that the density of sympathetic neurons is reduced.10 Moreover, the rate of extraction of NE by the failing heart is significantly reduced,25 26 perhaps amplifying the effect of increased nerve discharge rate on the local myocardial catecholamine concentration.
We tested the hypothesis that a component of the apparent cardiac sympathetic neurobiology of the failing heart could be explained by altered local production of NGF. Our study, for the first time, documents release of NGF from the healthy human heart, and, in association, we observed a marked reduction in the setting of heart failure. The plasma arterial concentration of NGF was also substantially lower in CHF patients. The mechanism for the latter observation is uncertain and is not addressed in the present study. An effect of anti–failure therapy could not be excluded because the effects of ACE inhibition and cardiac glycosides on NGF expression are unknown. To confirm these observations, in an experimental model of CHF, we examined the myocardial expression of NGF at both the mRNA and protein levels. Both techniques revealed a significant reduction in NGF synthesis in the failing heart, in noninfarcted tissue. In addition to the data indicating reduced NGF production, we confirmed the association between CHF and altered cardiac sympathetic innervation, as indicated by reduced catecholamine fluorescence and trkA mRNA expression.10 11
Having identified the heart as a source of NGF in both humans and
rodents, we investigated the cardiomyocyte as a potential
cellular source and examined the role of NE as a potential regulator of
NGF expression. NGF expression by cardiomyocytes was
readily detectable at both the mRNA and protein levels, and the
expression of NGF was significantly decreased by exposure to NE. This
effect appeared to be mediated via -adrenoceptors and involved the
PKC signaling system. The findings of our study differ from previous
studies of NGF regulation in some other cell types. Several groups have
reported induction of NGF in response to catecholamines in
glioma cells, fibroblasts, and vascular smooth muscle
cells,27 28 29 although others have suggested that the
response may vary in a growth-dependent manner.30
Furthermore, in contrast to our study, previous investigators have
suggested that the effects of catecholamines on NGF
expression are mediated via ß-adrenoceptor activation, with
subsequent involvement of the cAMP/PKA second messenger signaling
pathway.31 32 Involvement of PKC in NGF regulation has
also been suggested in some cell types. Phorbol 12-myristate
13-acetate has been shown to upregulate NGF expression in
fibroblasts.33 34 Given the directionally opposite effect
of NE on NGF expression in cardiomyocytes observed in our
study, these data suggest that this response may represent a
cell-specific response to prolonged NE exposure. For example both
experimental and clinical studies indicate that prolonged exposure to
catecholamines exerts adverse effects on the
myocardium.4 35 As a consequence, a reduction
in NGF expression in the myocardium with a consequent
reduction in sympathetic innervation density could represent an
adaptive response to prolonged exposure to elevated sympathetic tone.
However, it is also conceivable that alterations in tissue
catecholamine levels do not provide the sole stimulus for
the reduction in NGF expression.
In addition to the neurotrophic actions of NGF, other actions of importance to the myocardium have been recently suggested. Lockhart et al36 recently reported that NGF rapidly potentiated synaptic transmission between sympathetic neurons and cardiomyocytes in a coculture system. This action appeared to be mediated by neuronal tyrosine kinase receptors, although the specific intracellular mechanism responsible for this process remains uncertain. In a study by Wakade et al,37 it was demonstrated that both the expression of NE transporter mRNA and uptake-1 activity in chromaffin cells increased during exposure to NGF. This latter observation would be entirely in keeping with observations in the failing heart of reduced NGF synthesis and reduced NE reuptake.
Study Limitations
Although the data consistently indicate that NGF mRNA
expression and protein expression are reduced in both human and
experimental heart failure and in cardiomyocytes under the
influence of NE, precise quantification of the magnitude of the effect
on mRNA expression is not possible because of the semiquantitative
nature of the RT-PCR approach used in the present study.
Conclusions
In the present study, we have comprehensively examined the
regulation of NGF in the myocardium and highlighted its
potential role in the pathophysiological changes
that occur in the cardiac sympathetic nervous system in human and
experimental heart failure. The data indicate that in the failing
heart, a counterregulatory reduction in myocardial NGF expression
occurs, providing an explanation for the previously unexplained finding
of reduced sympathetic neuronal density.
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Acknowledgments |
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This study was supported by an Institute Grant from the National Health and Medical Research Council of Australia. Dr Kaye is the recipient of a Wellcome Trust Senior Research Fellowship. The technical advice and assistance of Drs Rodney Dilley and David Prior (Baker Medical Research Institute) are gratefully acknowledged.
Received December 9, 1999; accepted March 17, 2000.
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