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1B-adrenergic receptors after pressure overload in
mouse hearts
1 Cellular Biochemistry Laboratory, 2 Experimental Cardiology Laboratory, and 3 Molecular Physiology Laboratory, Baker Medical Research Institute, Prahran 3181, Victoria, Australia; and 4 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cardiac
hypertrophy and function were studied 6 wk after constriction of the
thoracic aorta (TAC) in transgenic (TG) mice expressing constitutively
active mutant 
1B-adrenergic receptors (ARs) in the
heart. Hearts from sham-operated TG animals and nontransgenic littermates (WT) were similar in size, but hearts from TAC/TG mice were
larger than those from TAC/WT mice, and atrial natriuretic peptide mRNA
expression was also higher. Lung weight was markedly increased in
TAC/TG animals, and the incidence of left atrial thrombus formation was
significantly higher. Ventricular contractility in anesthetized
animals, although it was increased in TAC/WT hearts, was unchanged in
TAC/TG hearts, implying cardiac decompensation and progression to
failure in TG mice. There was no increase in 1A-AR mRNA
expression in TAC/WT hearts, and expression was significantly reduced
in TAC/TG hearts. These findings show that cardiac expression of
constitutively actively mutant 1B-ARs is detrimental in
terms of hypertrophy and cardiac function after pressure overload and that increased 1A-AR mRNA expression is not a feature of
the hypertrophic response in this murine model.
1-adrenergic receptor; hypertrophy; heart failure; transgenic mouse; constitutively active mutant
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE MECHANISMS
INVOLVED in hypertrophic growth and the progression to heart
failure in vivo are poorly understood. Identifying the receptors
involved is a first step toward a better definition of the signaling
pathways regulating this cellular growth response. In experiments using
rat neonatal cardiomyocytes, stimulation with
1-adrenergic agonists leads to hypertrophy,
characterized by cell growth as well as increased expression of fetal
genes (10, 13, 22).
1-Adrenergic receptors (ARs) are classified into
1A-, 1B-, and 1D-subtypes;
the 1A- and 1B-subtypes are expressed in
the heart at the protein level (15, 31). In
rat neonatal cardiomyocytes, hypertrophic growth initiated by
1-adrenergic agonists or other factors is associated
with increased expression of 1A-AR mRNA together with
decreased expression of the 1B-AR mRNA, implying a
central role for receptors of the 1A-subtype (19). This supports previous pharmacological studies
(12). Furthermore, other studies showed that selective
activation of 1A-ARs was sufficient to induce all these
changes, including the reciprocal changes in 1A- and
1B-AR mRNA expression (4). Possibly of more
significance, hypertrophy of rat hearts in vivo after abdominal aortic
banding caused changes in 1-AR mRNA expression similar
to those described in neonatal cardiomyocytes, again suggesting an
activation of 1A-ARs (19).
Signaling pathways initiated by 1A- and
1B-ARs involve the activation of the heterotrimeric G
protein Gq (28), which is a well-established
mediator of hypertrophic growth in neonatal cardiomyocytes
(1) and in mouse hearts in vivo (3,
20). Thus it would seem likely that 1A- and
1B-ARs can initiate hypertrophic responses. Inasmuch as
there are no 1B-AR agonists with sufficient specificity,
it is not possible to evaluate the potential hypertrophic activity of
1B-ARs directly in isolated neonatal cardiomyocytes. Assessing direct cardiac hypertrophic actions of 1-AR
agonists in vivo would be rendered impossible by their pressor
activity, leading indirectly to myocardial hypertrophy. To overcome
these problems, we have used transgenic mice with cardiac-targeted
expression of constitutively active mutant (CAM) 1B-ARs;
thus 1B-AR stimulation is limited to the cardiomyocytes.
These mice express elevated levels of atrial natriuretic peptide (ANP)
mRNA and have been reported to be minimally hypertrophied (~20%
increase in heart weight) (16), pointing to a potential
growth-promoting action of these receptors in hearts in vivo.
The present study was undertaken to investigate the effects of the
expression of CAM 1B-ARs on the development of pressure overload hypertrophy caused by thoracic aortic constriction (TAC).
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
Parent transgenic mice expressing CAM (A288K, K290H, and A293L)
1B-ARs expressed under an -myosin heavy chain
(-MHC) promoter were generated at the Howard Hughes Medical
Institute (Duke University, Durham, NC) (16). Female
wild-type (WT) mice derived from F1 crosses of SJL and C57
strains were used to breed with heterozygotic male transgenic (TG)
mice. Southern blot hybridization of DNA extracted from tail biopsies
was used to screen animals for the transgene. WT littermates were used
as controls. Male and female mice aged 15-25 wk and weighing
20-30 g were used.
Surgery and TAC. Mice were anesthetized by intraperitoneal injection of a mixture of ketamine (8 mg/100 g), xylazine (2 mg/100 g), atropine (0.06 mg/100 g), and buprenorphine (0.2 mg/100 g). The chest was opened along the midline of the upper sternum. The segment of aortic arch between the right innominate and the left main carotid arteries was dissected, and the aortic diameter was narrowed by 70% (2). Sham-operated (SH) animals were treated similarly, except the aortic arch was not constricted. All experiments were carried out 6 wk after surgery.
Functional measurements. Mice were anesthetized as described above. Left ventricular (LV) function and arterial blood pressure were measured using a 1.4-F Millar microtip pressure transducer catheter that was inserted into the aorta via the right carotid artery and then advanced into the LV. Blood pressure, LV systolic pressure, LV end-diastolic pressure, and the maximum rate of isovolumic pressure development (dP/dtmax) and decay (dP/dtmin) were recorded using a Grass polygraph. Averages of hemodynamic data from 10 consecutive beats were used. In some animals the arterial blood pressure was simultaneously measured from the right and the left carotid arteries.
Identification of atrial thrombus and pleural effusion. Pleural effusion and atrial thrombus were detected under a surgical microscope. Before the heart was removed, the chest was opened via the diaphragm to avoid bleeding, and the chest cavities were inspected for fluid accumulation. Chronic thrombus was confirmed by its yellowish color and tight adhesion to the arterial wall. Each thrombus was carefully dissected and weighed.
Ventricular myocyte cross-sectional area. Cross-sectional area was measured in LV transverse sections as described previously (16), except sections were stained with Sirius red. From each heart, 8-10 fields were chosen from the epicardial layer, where myocytes originate longitudinally, and 8-15 cells per field were measured. The average of 70-100 myocytes was used. All measurements were made blinded.
Measurement of mRNA.
Total RNA was prepared from four groups of mouse LV (SH and TAC of WT
and TG groups) with use of the acid guanidinium
thiocyanate-phenol-chloroform procedure (6). Levels of
mRNA encoding 1A- and 1B-ARs, myosin light chain 2v isoform (MLC-2v), and ANP were measured by RNase protection analysis, as described previously (9). Probes
for the RNase protection assay were prepared exactly as described previously (4).
1-AR measurement.
Mouse hearts were homogenized in binding buffer (50 mM Tris · HCl and 10 mM MgSO4, pH 7.4) containing 0.25 M sucrose. The homogenate was centrifuged at 1,000 rpm for 10 min at 4°C, and the
supernatant was recentrifuged at 30,000 g for 30 min at
4°C, washed once, and resuspended in the binding buffer. Binding
assays included
2-[2-(4-hydroxy-3-3-[125I]iodophenyl)ethylaminomethyl]--tetralone
([125I]HEAT; 2,200 Ci/mmol, 40,000 cpm) together with
increasing concentrations of the selective antagonist KMD-3213 and were
carried out at room temperature for 1 h in a total volume of 200 µl. Bound [125I]HEAT was separated by rapid filtration
through Whatman GF/C filters, and the sample was washed then with 16 ml
of binding buffer. The dried filters were counted in a gamma counter.
[3H]inositol phosphate responses in LV strips.
LVs were dissected from mouse hearts under ice-cold saline, and thin
strips (15-20 mg) were mounted in siliconized 5-ml organ baths and
labeled with [3H]inositol (20 µCi/ml) for 4 h, and
the [3H]inositol phosphate (IP) response was
measured as described previously (27).
Chloroethylclonidine (CEC, 10 µM), an 1B-AR-selective alkaline agent, was added for the final 1 h of the labeling period and was washed out before agonist addition. [3H]IP
generation was terminated by freezing. Frozen tissues were weighed, and
[3H]IPs were extracted and quantified as described
previously (27).
Materials. Norepinephrine, phytic acid, and nucleotides were obtained from Sigma Chemical (St. Louis, MO) and [myo-2-3H]inositol (18 Ci/mmol) from the Radiochemical Centre Amersham (Buckinghamshire, UK). KMD-3213 was a gift from R. M. Graham. [125I]HEAT was purchased from New England Nuclear, Life Science (Boston, MA), and CEC and BMY-7378 from Research Biochemicals. A-61603, the active R-enantiomer of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronapthalen-1-yl] methane sulfonamide hydrobromide, was provided by Abbot Laboratories. All other chemicals were of analytic reagent grade, and reagents were dissolved in Milli-Q water.
Statistics. Values are means ± SE. Between-group differences were analyzed by one-way ANOVA followed by Fisher's protected least significant difference test for post hoc comparisons. Student's unpaired and paired t-tests were used for [3H]IP studies. Significance was determined at P < 0.05. Linear correlation and regression analysis were used for organ weights. Fisher's exact test was used for nonparametric data. Receptor binding data were analyzed using Allfit, providing "best-fit" values for receptor concentration and affinity.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Functional measurements and hypertrophic markers in WT and TG
hearts.
Functional measurements were carried out 6 wk after surgery in four
groups of mice: the SH and TAC of WT and TG groups. Because there were
no differences in body weight and tibial length between groups, the
organ weights are expressed as absolute values. Aortic blood pressures,
lung weight, and functional or morphometric parameters were similar in
SH/WT and SH/TG mice (Table 1). TAC
caused significant increases in systolic aortic pressure (measured
proximal to the constriction), LV systolic pressure, and LV
end-diastolic pressure, which were similar in WT and TG mice,
indicating a similar extent of pressure overload in the two groups
(Table 1).
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1B-ARs accelerated the development of heart failure
after TAC, whereas there was no sign of heart failure in WT mice. TAC
caused increases in dP/dtmax and
dP/dtmin in WT mice, indicating that hearts of
these mice were able to compensate for the increased pressure load.
Hearts from the CAM 1B-AR TG mice showed no such
increase in LV contractile function, implying cardiac decompensation
(Table 1).
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Expression of mRNA encoding 1A- and
1B-ARs.
Some models of cardiac hypertrophy are associated with an increased
expression of 1A-AR mRNA together with a decreased
1B-AR expression (4, 19). The
expression of mRNAs encoding 1A- and
1B-ARs was measured in LVs from WT and TG hearts after
TAC. There was no increase in the concentration of 1A-AR
mRNA with pressure overload hypertrophy in the WT hearts (Fig.
3). Furthermore, TAC in the TG hearts was
associated with a reduction in 1A-AR mRNA (Fig. 3).
Pressure overload hypertrophy did not cause any significant change in
expression of endogenous 1B-AR mRNA in WT hearts, where
it is expressed under the control of its own promoter.
1B-AR mRNA expressed under the control of an -MHC promoter was 30-fold higher in TG than in WT hearts. There was a
decrease in the content of 1B-AR mRNA in the
hypertrophied TG hearts, presumably reflecting downregulation of the
-MHC promoter used in the transgene construct (26).
Despite this decrease, the expression of 1B-AR mRNA
remained 20-fold higher in TG than in WT hearts (Fig. 3).
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1-AR binding in TG and WT hearts.
To further investigate alterations in 1-AR activity in
hypertrophied mouse hearts, 1-AR content was measured
using radioligand ([125I]HEAT) binding. The
subtype-selective antagonist KMD-3213 was used to distinguish
1A- and 1B-ARs. The affinity of this
antagonist for 1A-ARs is between 0.1 and 0.5 nM, whereas
the affinity for 1B- and 1D-ARs is
between 50 and 200 nM (21). In membranes prepared from rat
hearts, 20% of [125I]HEAT binding sites showed a
high-affinity binding of KMD-3213 (dissociation constant ~0.1 nM),
indicating that 20% of the 1-ARs are of the
1A-subtype (data not shown), as reported by others (15). In mouse hearts, KMD-3213 did not compete for
[125I]HEAT binding at <10 nM, and thus receptors with
1A-subtype specificity were not present at detectable
levels (Fig. 4). Therefore, it was not
possible to determine whether there was a reduced 1A-AR content in hypertrophied TG hearts, in parallel with the decreased mRNA
expression.
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1D-ARs to the
[125I]HEAT binding was evaluated using the
1D-AR-selective antagonist BMY-7378 (29, 32). BMY-7378 did not compete for binding at <100 nM
(data not shown) (29), eliminating any possible
contribution from 1D-ARs to the [125I]HEAT
binding sites.
1B-ARs were quantified as [125I]HEAT
binding sites with affinities for KMD-3213 at 50-200 nM
(21). The affinity for KMD-3213 in mouse heart membranes
was 107 ± 14 nM (n = 20). This value was similar
in all experimental groups. TG hearts contained approximately twofold
higher concentrations of 1B-ARs than WT hearts, as
previously reported (16). There was no significant change
in 1B-AR content with hypertrophy in the TG hearts,
despite the reduced mRNA expression. However, there was a small
reduction in the content of 1B-ARs in TAC/WT hearts
(Fig. 4).
IP responses in LVs of WT and TG hearts.
Because 1A-ARs were undetectable in receptor-binding
studies, experiments were undertaken to establish whether an
1A-AR contribution to signaling could be detected.
1-AR-stimulated phospholipase C (PLC) activity was
chosen as a proximal signaling event. PLC activity was measured as
total [3H]IP generation in LiCl-pretreated strips of
[3H]inositol-labeled LVs. The basal [3H]IP
labeling was higher in LVs from TG hearts than in LVs from WT hearts.
Furthermore, the stimulation by norepinephrine was higher, as expected
with CAM 1B-adrenergic receptor expression (Fig.
5, A vs. C).
Hypertrophy did not cause any significant alteration in these responses
(Fig. 5, C vs. D). In WT hearts, TAC increased [3H]IP content without any measurable change in the
norepinephrine response (Fig. 5, A vs. B).
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1A-selective antagonist A-61603. Thus there was no evidence for an involvement of 1A-ARs
in any of the groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study demonstrate that enhanced activity of
1B-ARs in the heart, induced by expressing a CAM
receptor, aggravates cardiac hypertrophy after TAC and accelerates the
development of heart failure. In SH animals, CAM 1B-AR
expression was not associated with measurable alterations in cardiac
function. However, hearts from TG animals were more sensitive to
pressure overload hypertrophy than nontransgenic controls. This was
shown primarily by the greater increase in heart weight and lung weight
after pressure overload in the TG mice than in the WT controls.
Although WT hearts responded to the demands of the increased afterload with an increase in contractility, no such increase was observed in the
TG animals, indicating that WT animals, but not TG animals, were able
to compensate for the pressure overload. The TG animals also showed a
higher incidence of pleural effusion and thrombus formation in the left
atria. Thus TG animals subjected to TAC showed more extensive
hypertrophy as well as ventricular dysfunction indicated by the failure
to increase contractility, higher incidences of pleural effusion and
atrial thrombus, and more severe lung congestion.
Hearts from CAM 1B-AR TG animals were previously
reported to be mildly hypertrophied (20% increase in heart weight and
cell size), even in the absence of an additional hypertrophic stimulus (16). In our hands, however, SH/TG mice had heart weights
and ventricular myocyte cross-sectional areas not different from SH/WT mice. This difference most likely reflects some aspect of the housing
or the diet to which the animals were subjected, because the animals
had been exchanged between the two laboratories and regained the
phenotype of the host laboratory. The differences in ANP mRNA between
WT and TG hearts, however, were similar in animals housed in either
facility (16). TG mice overexpressing WT
1B-ARs have been reported to show no hypertrophy in
terms of heart weight but have an elevated expression of ANP mRNA
(3). It is possible that the increased ANP expression is a
contributor to heart failure. However, mice with elimination of ANP
expression or cardiac-targeted overexpression show significant changes
in blood pressure but not in cardiac function (5,
14).
Although the present study provides evidence that CAM
1B-ARs exacerbate hypertrophy and function after TAC, a
number of studies have suggested a central role of 1A-AR
in the development of hypertrophy. In rat neonatal cardiomyocytes,
hypertrophic responses initiated by 1-adrenergic
agonists, endothelin-1 or phorbol 12-myristate 13-acetate, were shown
to be associated with an increased expression of 1A-AR
mRNA together with a decrease in 1B-AR mRNA
(19). Subsequent studies in our laboratory showed that
selective stimulation of 1A-ARs was sufficient to cause
not only hypertrophy but also the changes in 1A- and
1B-AR mRNA (4). Furthermore, similar changes were observed in cardiomyocytes derived from rat hearts after
abdominal aortic banding (19). This suggested that the transcriptional induction of the 1A-AR could be a
universal feature of the hypertrophic phenotype. In contrast, the
present study has demonstrated that 1A-AR mRNA is not
increased with the establishment of pressure overload hypertrophy in WT
mice. Furthermore, the 1A-AR mRNA expression was
significantly reduced, rather than increased, in the severely
hypertrophied TG hearts (Fig. 3). These differences might reflect the
different model systems used. Importantly, abdominal aortic
constriction causes peripheral hypertension (18), and this
does not occur after TAC (24). It is also possible that
the data reflect mechanisms in the rat heart that are different from
those in the mouse heart. 1-ARs are more highly
expressed in the rat heart than in the mouse heart: 20-100 fmol/mg
protein in the rat heart (15, 17) compared
with 3-10 fmol/mg in the mouse heart (16,
17, 31) (Fig. 3). Furthermore,
1A-ARs account for ~20% of the 1-AR
population in rat hearts (unpublished data) (15) but were
undetectable in mouse hearts in this and other studies (Fig. 4)
(31), indicating that they represent less than ~15% of
total 1-ARs. Thus the contribution of
1A-ARs to overall 1-adrenergic responses
appears to be smaller in the mouse than in rat heart, and this
difference may underlie the disparate 1-AR mRNA
responses to hypertrophic stimuli. In the human heart,
1A-ARs contribute 70-90% of the
1-AR mRNA (8), and the relative
contribution of the 1A- and 1B-ARs to
hypertrophic growth may thus differ from that in rat and mouse hearts.
However, the data presented in the present study, together with
previous findings (4, 19), show that
1A- or 1B-ARs can contribute to the
overall hypertrophic response.
As well as showing increased 1A-AR mRNA, studies in rat
neonatal cardiomyocytes showed reduced levels of mRNA encoding
1B-ARs. No such decrease was observed in hypertrophied
WT mouse hearts when this was expressed under its endogenous promoter.
There was, however, a small decrease in 1B-AR content as
measured by ligand binding, suggesting some reduction in
1B-AR activity in hypertrophied mouse hearts.
1B-AR mRNA was reduced in the TAC/TG hearts. These receptors are expressed under an -MHC promoter, and downregulation of the -MHC has been reported previously in failing hearts
(26). This finding may therefore reflect an action on the
-MHC promoter used in the construction of the transgene. Our recent
studies suggest that endogenous -MHC, as well as transgenes
expressed under the exogenous -MHC promoter, is downregulated
similarly in failing mouse hearts (unpublished data). Even with such
downregulation, the level of expression of the 1B-AR
mRNA remained 20-fold higher than in WT animals, and there was no
decrease in receptor binding (Fig. 4).
Both 1A- and 1B-ARs couple via
Gq to PLC-
isoforms and can also couple to
Gi. Thus both have the potential to initiate a wide range
of effectors that respond to G protein 
-subunits in addition to
those mediated by the -subunits of Gq and Gi
(8, 23, 25).
1A-ARs couple more efficiently than
1B-ARs to Gq (23) and thus
might be expected to activate PLC-dependent pathways more effectively
than 1B-ARs. However, the relative importance of the two
receptor subtypes in activating PLC appears to vary between cardiac
preparations. In rat neonatal cardiomyocytes, 1A-ARs
have been reported to be primarily responsible for IP responses
(25), whereas in intact rabbit (30) or mouse
hearts (9), 1B-ARs appear to be
predominant. Other studies have reported an interaction between
1A- and 1B-ARs, such that the
1B-subtype inhibits the activation of the
1A-ARs and reduces Ca2+ signaling
(7). The two 1-AR subtypes appear to have
different selectivities for G protein -subunits and to activate
mitogen-activated protein kinase pathways by different mechanisms
(11). Thus, although it is clear that 1A-
and 1B-ARs can exacerbate hypertrophic responses, the
mechanisms involved may not be identical.
In summary, the expression of CAM 1B-ARs sensitizes the
heart to the development of pressure overload hypertrophy and
facilitates the transition from compensated hypertrophy to failure. The
development of pressure overload hypertrophy in mice was not associated
with any detectable increase in 1A-AR expression or
function. Thus increased 1A-AR activity is not a
universal feature of hypertrophy.
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ACKNOWLEDGEMENTS |
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We thank Dr. R. J. Lefkowitz for supplying the transgenic mice, Brian Jones for imaging, and Dr. Rod Dilley for assistance with the morphology.
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FOOTNOTES |
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This work was supported by the Australian National Health and Medical Research Council and the National Heart Foundation of Australia.
Address for reprint requests and other correspondence: E. A. Woodcock, Baker Medical Research Institute, Commercial Rd., Prahran 3181, Victoria, Australia (E-mail: liz.woodcock{at}baker.edu.au).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 12 October 1999; accepted in final form 9 March 2000.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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