© 1997 American Heart Association, Inc.
Articles |
Cross Talk Between Angiotensin AT1 and 
1-Adrenergic Receptors
Angiotensin II Downregulates 1a-Adrenergic Receptor Subtype mRNA and Density in Neonatal Rat Cardiac Myocytes
From the Cardiology Section, Veterans Affairs Medical Center, the Cardiovascular Research Institute, and the Department of Medicine, University of California, San Francisco.
Correspondence to Joel S. Karliner, MD, Cardiology Section (111C), Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121. E-mail Karliner.Joel-S{at}SanFrancisco.VA.Gov
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Abstract Signaling mediated by the angiotensin (Ang) II and
1-adrenergic receptor (1-AR)
pathways is important for cardiovascular homeostasis.
However, it is unknown whether Ang II has any direct effect on
1-AR expression and signaling in cardiac myocytes. In
the present study, we determined 1-AR subtype mRNA
levels by RNase protection; receptor density by competition binding
with 5-methylurapidil; and 1-AR mediated
c-fos expression by Northern blot analysis. We found
that Ang II had no effect on 1b- and
1d-AR mRNA levels but decreased the 1a-AR
mRNA level in a time- and dose-dependent manner. The maximal effect
occurred at 6 hours with 100 nmol/L Ang II (40.0±8.2% reduction, n=4,
P<.01). The decrease in 1a-AR mRNA level
induced by Ang II is mediated by the Ang II AT1
receptor subtype and is associated with decreased stability of
1a-AR mRNA. Corresponding to the changes in the
1a-AR mRNA level, Ang II (100 nmol/L, 24 hours) reduced
the density of high-affinity sites for 5-methylurapidil
(1A-AR) by 29% (56.5±6.4 versus 79.0±11.6 fmol/mg
protein, n=4, P<.05). 1-AR stimulated
c-fos induction, which could be blocked by 5-methylurapidil
but not by chloroethylclonidine, was attenuated by Ang II preincubation
(100 nmol/L, 24 hours). We conclude that there is previously
undescribed cross talk between AT1 receptors and
1-ARs. Ang II selectively downregulates
1a-AR subtype mRNA and its corresponding receptor as
well as 1a-AR mediated expression of the
immediate-early gene c-fos in cardiac myocytes.
Key Words: 1-adrenergic receptor • angiotensin II • cardiac myocyte • immediate-early gene
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Angiotensin II plays a principal role in mediating the physiological actions of the renin-angiotensin system, which is critical for cardiovascular homeostasis. Ang II also contributes to the pathogenesis of hypertension, arterial disease, cardiac hypertrophy, heart failure, and diabetic renal disease.1 At least two major subtypes of the Ang II receptor, AT1 and AT2, have been identified by molecular cloning and nonpeptidic isoform-specific antagonists. The AT1 but not the AT2 receptor subtype mediates Ang II stimulated pressor effects and growth of vascular smooth muscle cells and cardiac myocytes.2 3 4 5 Thus, AT1 receptor blockade by AT1 antagonists6 or reduction of Ang II synthesis by angiotensin-converting enzyme inhibitors7 leads to the lowering of blood pressure and regression of cardiac hypertrophy.
Acute stimulation of cardiac 1-ARs by neurotransmitters
such as NE and epinephrine induces positive inotropic effects
and electrophysiological alterations,
whereas chronic stimulation of cardiac 1-ARs leads to
cardiac hypertrophy. Recently, three 1-AR
subtype mRNAs (1a, 1b, and
1d) have been demonstrated in both neonatal and adult
rat cardiac myocytes by a sensitive RNase protection
assay.8 9 These 1-AR subtype mRNAs and
their corresponding receptors are differentially regulated by
agonists10 and interventions such as chronic
hypoxia11 and may support separate functions
within the cell.
Physiologically important interactions between
the angiotensin and adrenergic receptor systems have been
described. Ang II facilitates neurotransmitter release from the
presynaptic nerve terminals, which can cause vasoconstriction and
myocardial damage.12 13 14 15 Furthermore, important
interactions between AT1 receptors and 1-ARs
also exist. In neurons, released NE interacts with
1-ARs, and their chronic activation in turn results in
the downregulation of AT1 receptors.16 This
cross talk between AT1 and 1-ARs is lacking
in neurons of the spontaneously hypertensive rat brain.17
A recent study has shown that Ang II induces transcription and
expression of 1-ARs in rat smooth vascular muscle
cells.18 However, it is unknown whether Ang II has any
direct effect on 1-AR expression and signaling in
cardiac myocytes, particularly on the 1a-AR subtype;
this potential interaction has not previously been investigated in any
tissue.
Our objectives in the present study were to determine (1) whether
Ang II regulates 1-AR subtype mRNA levels and density in
neonatal rat ventricular myocytes and (2) whether Ang II
influences 1-AR mediated signaling. Our data
indicate that in neonatal rat cardiac myocytes, Ang II selectively
downregulates 1a-AR subtype mRNA and its corresponding
receptors as well as 1a-AR mediated expression of
the immediate-early gene c-fos.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell Culture
Primary cultures were composed of single isolated ventricular myocytes prepared from the hearts of 1-day-old rats as previously described.19 Cells were plated onto 100-mm plastic dishes and attached at a final density of 100 to 150 cells/mm2 after overnight incubation. The medium was supplemented with 1.5 µmol/L vitamin B12 and 50 U/mL penicillin. The medium was changed routinely on culture day 1 to serum-free medium containing 10 µg/mL insulin and 10 µg/mL transferrin. Through culture day 3, the medium also contained 0.1 mmol/L bromodeoxyuridine to prevent nonmyocardial cell proliferation as previously reported.19 Treatment with Ang II or vehicle was started at day 4 after the medium was changed.
Cardiac nonmyocyte cultures were prepared as previously described.20 For conditioned medium production, cardiac nonmyocytes obtained during the preplating step of the myocyte isolation procedure were maintained in serum-supplemented medium (5% bovine serum) and allowed to proliferate to subconfluence. The subconfluent cultures were washed extensively with serum-free medium. After incubation in serum-free medium for 24 hours, cells were washed again with serum-free medium, and 10 mL serum-free medium was added per 100-mm dish. This medium was then conditioned with either Ang II or vehicle for 6 hours. Mock-conditioned dishes without cells were also similarly treated over the same time period and used as controls.
RNA Isolation and Northern Blot Hybridization
Total cellular RNA was extracted from cultured neonatal rat
cardiac myocytes using the guanidinium isocyanate
method.21 RNA concentration and purity were determined by
measuring absorbance at 260 and 280 nm using a spectrophotometer (model
DU-65, Beckman Instruments, Inc). For Northern blot analysis,
10 to 15 µg total RNA was fractionated by 1% agarose gel
electrophoresis and transferred to a nylon filter by capillary
blotting. The blot was prehybridized at 55°C for 4 hours and
hybridized at 55°C for 16 hours to rat c-fos or ß-actin
probes that were labeled by [32P]dCTP using the random
primer extension method with a random-primer DNA-labeling kit (RPAII
kit, Ambion, Inc). After hybridization, the filter was washed in 2x
SSC/0.1% SDS for 15 minutes, once at 55°C and once at room
temperature. The filter was exposed at -70°C with an intensifying
screen for 6 to 16 hours. The autoradiograms were
scanned using a laser densitometer. The amount of c-fos mRNA
was quantified relative to the amount of ß-actin mRNA on the same
filter. Preliminary experiments indicated that interventions with Ang
II, NE, chloroethylclonidine, 5-methylurapidil, and prazosin had no
significant effects on ß-actin mRNA signals.
RNase Protection Assay
RNase protection assays were performed as previously
described.11 Antisense RNA probes were labeled by
incorporation of [-32P]UTP into the RNA during
transcription with T7 RNA polymerase using the Maxiscript
kit (Ambion) and were gel-isolated after denaturing
polyacrylamide electrophoresis. The DNA templates for antisense
RNA probes were as follows: for 1d, a fragment of rat
brain 1d cDNA, including nucleotides 2025 to
224122 ; for 1b, a fragment of an
1b cDNA, including nucleotides 1002 to
125923 ; and for 1a, a fragment of rat
cardiac 1a cDNA,8 corresponding to
nucleotides 770 to 1084 of the human 1a
subtype.24 Sizes of the probes/protected fragments were as
follows: 1d, 267/217; 1b, 321/257; and
1a, 408/305. A ß-actin antisense RNA probe (Ambion,
Inc) was used to assess RNA loading and quality. The size of probe and
protected fragment of ß-actin were 180 and 126 bp, respectively.
The RPAII kit (Ambion, Inc) was used for both hybridization and RNase
digestion. Labeled probes (5 to 10x105 cpm) were
hybridized in solution with 20 to 40 µg of total RNA for 12 to 16
hours (58°C). Unhybridized single-stranded RNA was digested with
RNase A and T1 (1:40). Protected RNA RNA hybrids were
resolved on a 5% denaturing acrylamide gel and visualized
by autoradiography. In all experiments, in vitro
transcribed 1-AR subtype sense cRNAs served as a
positive control, and tRNA served as a negative control. The
hybridization signal for protected RNA fragments was quantified by
counting the excised gel band in a scintillation counter.
Radioligand Binding Assay
Displacement binding experiments using 125I-HEAT and
varying concentrations of the 1A subtype selective
antagonist 5-methylurapidil were performed to determine
1-AR subtype distribution and density.11
After incubation with Ang II or vehicle for 2 to 24 hours, dishes were
washed three times with ice-cold MEM with HBSS and one time with PBS
and were scraped in harvesting buffer (50 mmol/L Tris-HCl,
150 mmol/L NaCl, and 5 mmol/L EDTA, pH 7.5).
The cell mixture was centrifuged at 100 000g for 1
hour at 4°C. The pellet was resuspended in harvesting buffer and
sonicated for 15 seconds. The particulate preparation then was
incubated in triplicate with 100 pmol/L 125I-HEAT
and 20 concentrations of 5-methylurapidil (1 pmol/L to
100 µmol/L) in a total volume of 100 µL containing
70 000 to 100 000 cells at 37°C for 30 minutes. Radioactivity was
determined in a gamma counter at a counting efficiency of 73%. The
best two-site fit for each binding curve was calculated by minimization
of the sum of squares of the errors, using nonlinear regression
analysis.25 Two-site and one-site models were
compared to determine whether the increase in the goodness of fit was
significantly more than would be expected on the basis of chance alone,
using a partial F test. A value of P<.05 was considered
significant. The 1-AR subtype density was normalized to
protein concentration determined by the method of
Bradford.26
Chemicals
125I-HEAT (2200 Ci/mmol),
[-32P]dCTP (2000 Ci/mmol), and
[-32P]UTP (800 Ci/mmol) were obtained from Amersham.
Losartan was a gift from W. Henckler at Merck & Co, Inc.
TGF-ß1 was from R&D Systems. Prazosin, 5-methylurapidil,
and PD123319 were from RBI. Ang II, actinomycin D, and all other
reagents were from Sigma Chemical Co.
Statistical Analysis
All data are expressed as mean±SE. Comparison of numerical data
was by the Student's t test for paired observations between
two groups and by ANOVA followed by Dunnett's test when more than two
groups were analyzed. A value of P<.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Effects of Ang II on
1-AR Subtype mRNA
LevelsWe used RNase protection assays to measure
1-AR
subtype mRNA levels in total RNA extracted from neonatal rat cardiac
myocytes incubated with Ang II or vehicle for 2 to 24 hours.
Representative autoradiograms from
RNase protection assays are shown in Fig 1A
. Ang II incubation (100
nmol/L, 2 to 24 hours) had no significant effect on
1b- and 1d-AR mRNA levels but
significantly reduced the 1a-AR mRNA level (Fig 1B). The
inhibitory effect of Ang II on 1a-AR
mRNA levels was dose dependent (Fig 1C).
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), 
), and
) quantified by counting the excised gel bands
in a scintillation counter and expressed as a percentage of the level
in control cells at identical time points. The data depicted are the
mean±SE from four separate experiments. *P<.05 vs control.
C, Dose-dependent effect of Ang II on
To determine whether the decrease in 1a-AR mRNA level
induced by Ang II was mediated by the AT1 or
AT2 subtype, we examined the effects of PD123319 and
losartan on the Ang II induced decrease in
1a-AR mRNA level. The Ang II induced decrease
in 1a-AR mRNA level was blocked by losartan but
not by PD123319 (Fig 2). This observation
indicates that Ang II induces the decrease in 1a-AR
mRNA level by its effects on the AT1 but not the
AT2 subtype.
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The decrease in 1a-AR mRNA level induced by Ang II
could result from either an inactivation of 1a-AR gene
transcription or an increased rate of 1a-AR mRNA
degradation. Therefore, we compared the degradation rate of
1a-AR mRNA in the presence of the transcription
inhibitor actinomycin D in control and Ang
II treated cells. Preliminary experiments showed that 0.05
µg/mL actinomycin D had no effect on cell viability over 12
hours but inhibited transcription by >95% within 3 hours, as assayed
by [3H]uridine incorporation into total RNA (data not
shown). When transcription was inhibited by actinomycin D, Ang II
treatment decreased the 1a-AR mRNA signal (Fig 3). The half-lives for
1a-AR mRNA were 4.3±0.7 and 3.2±0.4 hours for control
and Ang II treated cells, respectively (P<.01).
These results indicate that decreased stability of 1a-AR
mRNA could contribute to the decrease in 1a-AR mRNA
level induced by Ang II.
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Because myocyte cultures are contaminated with 5% to 10%
nonmyocytes and because Ang II induces the release of
TGF-ß1 from nonmyocytes,27 we
hypothesized that Ang II might reduce the 1a-AR
mRNA level of cardiac myocytes in a paracrine fashion. Therefore, we
examined the effects of both Ang II conditioned medium from
nonmyocytes and TGF-ß1 alone on
1a-AR mRNA levels in cardiac myocytes. Conditioned
medium from nonmyocytes stimulated with Ang II for 6 hours
induced a modest but significant increase in the 1a-AR
mRNA level, whereas TGF-ß1 (0.1 to 10 ng/mL) had
no effect on 1a-AR mRNA (Fig 4).
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Effects of Ang II on 1-AR Subtype Distribution
and Density
To test the hypothesis that a decreased 1a-AR
subtype mRNA level led to decreases in 1A-AR subtype
number, the selective 1A-AR subtype
antagonist 5-methylurapidil was used in competition
radioligand binding assays. Ang II incubation (100
nmol/L, 2 to 24 hours) had no effect on the density of
low-affinity sites (1B-AR, corresponding to
the cloned 1b- and 1d-ARs, Fig 5). By contrast, Ang II reduced the
density of high-affinity sites (1A-AR, corresponding to
the cloned 1a-AR) in a time-dependent manner.
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Influence of Ang II on 1-AR Mediated
c-fos Induction
To determine the effects of reduced expression of
1-ARs on early gene expression, we measured
1-AR stimulated c-fos mRNA expression in
Ang II pretreated cells. Ang II pretreatment (100
nmol/L, 24 hours) decreased NE-stimulated c-fos mRNA
expression in the presence of a ß-AR antagonist,
(-)-propranolol (Fig 6),
suggesting an effect mediated by 1-ARs.
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To further determine whether 1-AR stimulated
c-fos expression was mediated by the 1A- or
1B-AR subtype, we examined the effects of
5-methylurapidil and chloroethylclonidine on NE-stimulated
c-fos induction. NE-stimulated c-fos mRNA
expression was blocked by 5-methylurapidil but not by
chloroethylclonidine in both control and Ang II pretreated
cells (Fig 7). This observation indicates
that 1-AR induced c-fos mRNA expression
is mediated by the 1A- but not by the
1B-AR subtype.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Of the >100 receptors that are coupled to G proteins, adrenergic receptors have often been used as prototypes for studying receptor gene regulation.28 For example, regulation of adrenergic receptors by agonists has been extensively examined.29 30 Cross regulation of receptor genes between G protein coupled receptors has also been described previously.31 Activation of both AT1 and
1-ARs involves G proteins,
and their respective signaling cascades are important for mediating
cardiovascular homeostasis. Interaction between
AT1 and 1-ARs in rat smooth vascular muscle
cells has been recently reported.18 In this cell type,
Ang II induces transcription and expression of 1b-
and 1d-ARs.18 However, it is unknown
whether Ang II has any effect on 1-AR expression
and signaling in cardiac myocytes, particularly on the
1a-AR, the subtype that mediates cardiac
hypertrophy32 33 ; this potential interaction
has not previously been investigated in any tissue. In the present
study, we sought to determine the effect of Ang II on
1-AR subtype mRNAs and density and on
1-AR mediated mRNA expression of the immediate-early
gene c-fos in cultured neonatal rat cardiac myocytes. The
major findings of the present study indicate that Ang II
selectively downregulates 1a-AR subtype mRNA and its
corresponding receptor as well as 1a-AR mediated
c-fos expression in neonatal rat cardiac myocytes. Our data
suggest that there is previously undescribed cross talk between
AT1 and 1-adrenergic receptors in cardiac
myocytes.
Alterations in gene transcription and mRNA stability are two major
mechanisms responsible for changes in the steady state mRNA levels of
adrenergic receptors. Regulation of mRNA appears to vary among cell
types and may also be species specific. For example, the mechanism of
downregulation of 1b-AR mRNA induced by
agonists34 and upregulation induced by
cycloheximide35 and glucocorticoids36 is
likely to be transcriptional. In rat smooth vascular smooth muscle
cells, Ang II increased 1d-AR mRNA
through transcriptional regulation,18 and in neonatal rat
cardiac myocytes, both the agonist-induced upregulation of
1a-AR and downregulation of
1b- and 1d-AR
mRNAs resulted from alterations in transcription.10 In
contrast, in DDT1 MF-2 smooth muscle cells, the mechanism
of agonist-induced downregulation of ß2-AR mRNA was shown
to be the destabilization of preexisting mRNA,31 and in
rabbit smooth vascular muscle cells, a phorbol ester and NE decreased
the 1b-AR mRNA level by
destabilization.37 In the present study, we have found
that the half-life of 1a-AR mRNA in Ang
II treated cells was shorter than in control cells. Furthermore,
when gene transcription was blocked by actinomycin D, the maximal
decrease in 1a-AR mRNA in Ang
II treated cells (42% at 2 hours) was similar to the maximal
decrease in the absence of the transcriptional inhibitor
(40% at 6 hours). These results suggest that the decrease in the
1a-AR mRNA level induced by Ang II in
cardiac myocytes is mediated primarily by a decrease in
1a-AR mRNA stability.
G protein–coupled receptors are differentially distributed in cardiac
myocytes and fibroblasts.3 4 5 8 38 39 40 For example, in
neonatal rat, 1-ARs are abundant in cardiac myocytes but
absent in cardiac fibroblasts,8 whereas
ß2-ARs predominate in cardiac fibroblasts.38
Whether cardiac myocytes have Ang II receptors is still a matter
of controversy. Although there is considerable evidence favoring the
presence of Ang II receptors on cardiac myocytes,3 4 5
recent studies suggest that the bulk of Ang II receptors in the
heart are located on cardiac fibroblasts.39 40 Ang II
stimulates the autocrine/paracrine release of growth factors. In rat
vascular smooth muscle cells, Ang II induces the autocrine release
of platelet-derived growth factor and
TGF-ß1.41 One mechanism by which Ang II
stimulates cardiac myocyte hypertrophy is by causing
release of molecules such as TGF-ß1 from cardiac
fibroblasts.27 42 Thus, in cardiac myocytes, Ang II
may influence 1a-AR mRNA production
or stability by producing one or more factors, either in an autocrine
or paracrine fashion. Accordingly, we attempted to ascertain whether
conditioned media from Ang II stimulated cardiac fibroblasts
or direct application of TGF-ß1 to cardiac myocytes would
influence 1a-AR subtype mRNA, but the
results of these experiments were unrevealing. Indeed, conditioned
medium from Ang II stimulated cardiac nonmyocytes
augmented rather than decreased 1a-AR mRNA.
These observations do not exclude an important direct effect of
Ang II on the regulation of 1a-AR mRNA
in cardiac myocytes. However, these data are consistent with
the possibility that the reduced mRNA stability caused by Ang II
(via a mechanism as yet unidentified) plays a major role in this
process.
In vivo animal studies have shown that Ang II enhances adrenergic
receptor function, resulting in increased vasoconstriction and
myocardial damage.15 43 44 45 On the basis of these reports,
we hypothesized that Ang II might regulate 1-ARs in
cardiac myocytes. However, we were surprised to find that this
regulation of 1-AR subtypes by Ang II is selective;
ie, Ang II had no effect on 1b- and
1d-AR subtype mRNA levels and their corresponding
receptor density but reduced 1a-AR subtype mRNA level
and its corresponding receptor density. This influence appears to be a
direct action of Ang II on 1-ARs. In contrast,
Ang II raises circulating NE concentration in intact
animals,12 13 14 15 46 thereby stimulating adrenergic
receptors.
Currently available pharmacological antagonists are not
sufficiently selective to identify the three distinct cloned receptor
subtypes (1a, 1b, and 1d).
For example, 5-methylurapidil, which was used in the present study,
can differentiate the cloned 1a-AR from the cloned
1b- and 1d-ARs but cannot differentiate
between the latter two cloned subtypes.47 48 49 Thus, the
high-affinity sites (pharmacologically defined 1A-ARs)
for 5-methylurapidil correspond to the cloned 1a-AR, and
the low-affinity sites (pharmacologically defined
1B-ARs) correspond to the cloned 1b- and
1d-ARs. Our finding that Ang II induced a decrease
in both the 1a-AR mRNA level and the density of
high-affinity sites for 5-methylurapidil suggests that the decreased
1a-AR mRNA level transduces a decrease in its
corresponding receptor density. Moreover, unchanged 1b-
and 1d-AR mRNA levels after Ang II treatment are
consistent with stability in their corresponding receptor
density, ie, the low-affinity sites for 5-methylurapidil.
The lack of effect of Ang II on 1b- and
1d-AR subtype mRNA levels and on their
corresponding receptor density differs from a report in rat vascular
smooth muscle cells,18 in which Ang II incubation
increased 1-AR density and
1b- and 1d-AR
mRNA levels (the 1a-AR mRNA signal was not examined).
Expression of 1-AR subtype mRNAs is tissue and cell
specific,8 9 and regulation of 1-AR mRNAs
by agonists is also different in different cells. For example,
1b-AR mRNA is markedly reduced in cardiac
myocytes by NE,10 whereas it is only reduced minimally in
DDT1 MF-2 cells31 or not at all in rabbit
smooth vascular muscle cells37 during prolonged exposure
to catecholamines (>24 hours). Thus 1-AR
subtype gene control is also likely to be cell-type specific. The
effect of Ang II differs from that of other hypertrophic agonists,
such as NE, endothelin-1, prostaglandin
F2, and phorbol esters, and from the effect
of pressure overload in vivo: these interventions repress
1b and 1d but
increase 1a mRNA.10 However,
incubation with Ang II produces results similar to the effect of
chronic hypoxia, which also has no influence on
1b- and 1d-AR
subtype mRNA levels and their corresponding receptors but reduces
1a-AR subtype mRNA level and its
corresponding receptor.11
The pharmacologically defined 1A-AR but not
1B-AR is believed to mediate cardiac
hypertrophy.32 33 Since Ang II decreases
1a-AR expression, we postulate that it may
also inhibit 1-AR stimulated hypertrophy
of cardiac myocytes. Cardiac hypertrophy induced by NE,
Ang II, endothelin-1, and basic fibroblast growth factor as well
as by hemodynamic load is associated with induction of
immediate-early genes, such as c-fos, c-jun, and
c-myc, which is followed by activation of fetal-type genes,
such as atrial natriuretic factor, skeletal -actin, and
ß-myosin heavy chain genes.50 51 52 In the present
study, we examined the effect of Ang II pretreatment on
1-AR mediated c-fos mRNA induction, and
we found that Ang II, itself a growth factor, reduced
1a-AR mediated
c-fos mRNA expression. This result suggests that Ang II
may act in part as a negative modulator of
1a-AR stimulated
hypertrophy.
In summary, the present study demonstrates for the first time that
there is receptor cross talk between AT1 and
1-ARs in cardiac myocytes. Ang II selectively
downregulates 1a-AR subtype mRNA and its
corresponding receptor as well as
1a-AR mediated expression of the
immediate-early gene c-fos. Our data also suggest the
intriguing possibility that the hypertrophic effect of Ang II may
be countered in part by its attenuating effect on 1-AR
gene expression, receptors, and signaling.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Research Service, Department of Veterans Affairs, and Program Project grant HL-25847 from the National Heart, Lung, and Blood Institute.
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Footnotes |
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Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10-13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-289).
Received February 10, 1997; accepted June 25, 1997.
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