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Circulation. 2000;101:71-77

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(Circulation. 2000;101:71.)
© 2000 American Heart Association, Inc.


Basic Science Reports

ß2-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis

Xiao-Jun Du, MBBS, PhD; Dominic J. Autelitano, PhD; Rodney J. Dilley, PhD; Binghui Wang, PhD; Anthony M. Dart, FRCP, PhD; Elizabeth A. Woodcock, PhD

From the Baker Medical Research Institute, Melbourne, Australia.

Correspondence to X.-J. Du, Baker Medical Research Institute, St Kilda Road Central, PO Box 6492, Melbourne 8008, Victoria, Australia. E-mail xiaojun.du{at}baker.edu.au


*    Abstract
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Background—ß-Adrenergic signaling is downregulated in the failing heart, and the significance of such change remains unclear.

Methods and Results—To address the role of ß-adrenergic dysfunction in heart failure (HF), aortic stenosis (AS) was induced in wild-type (WT) and transgenic (TG) mice with cardiac targeted overexpression of ß2-adrenergic receptors (ARs), and animals were studied 9 weeks later. The extents of increase in systolic arterial pressure (P<0.01 versus controls), left ventricular (LV) hypertrophy (TG, 94±6 to 175±7 mg; WT, 110±6 to 168±10 mg; both P<0.01), and expression of ANP mRNA were similar between TG and WT mice with AS. TG mice had higher incidences of premature death and critical illness due to heart failure (75% versus 23%), pleural effusion (81% versus 45%), and left atrial thrombosis (81% versus 36%, all P<0.05). A more extensive focal fibrosis was found in the hypertrophied LV of TG mice (P<0.05). These findings indicate a more severe LV dysfunction in TG mice. In sham-operated mice, LV dP/dtmax and heart rate were markedly higher in TG than WT mice (both P<0.01). dP/dtmax was lower in both AS groups than in sham-operated controls, and this tended to be more pronounced in TG than WT mice (-32±5% versus -16±6%, P=0.059), although dP/dtmax remained higher in TG than WT groups (P<0.05).

Conclusions—Elevated cardiac ß-adrenergic activity by ß2-AR overexpression leads to functional deterioration after pressure overload.


Key Words: genetics • receptors, adrenergic, beta • hypertrophy • heart failure • pressure


*    Introduction
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up arrowAbstract
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Under conditions of heart failure (HF), the ß-adrenergic pathway is markedly attenuated through the downregulation and uncoupling of ß1-adrenergic receptors (ARs).1 This involves receptor phosphorylation by ß-AR kinase (ßARK1, GRK-2) and the subsequent binding of receptors with ß-arrestins.1 2 3 In the failing myocardium, ß1-AR mRNA levels are reduced and the expression of ßARK and ß-arrestins is increased.1 3 4 5 ß2-AR density remains unchanged, but uncoupling of ß2-ARs has been reported.1 2 3 5 Other related changes include reduction in stimulatory GTP-binding protein (Gs),1 2 3 suppressed activity of adenylyl cyclase,1 2 and upregulation of inhibitory G protein (Gi).1 6

The significance of the changes to the ß-adrenergic system in HF, however, is not clear. There are 2 opposing views. One position is that the attenuated ß-adrenergic pathway in the failing heart protects against adrenergic overstimulation and therefore is salutary. Accordingly, the beneficial effects of ß-blockade in the treatment of HF could be due to further prevention of such overstimulation. The other view holds that the changes seen in the ß-adrenergic system are responsible for the loss of adrenergic support of myocardial contractility and therefore contribute to the progression and worsening of HF. This view is consistent with the poor tolerance of NYHA class IV patients to ß-blockers and the decline in cardiac function in HF patients in the early phase of ß-blocker therapy.7 Studies have also shown that the failing human myocardium generates nearly normal tension when stimulated with Ca2+ or cardiac digitalis, but the inotropic responses to activators of ß-AR and adenylyl cyclase are blunted.1 2 All of these findings imply an importance of functional support by the ß-adrenergic system in the failing heart. From this point of view, the possible mechanism of protection afforded by ß-blockade in chronic HF patients could be the partial reversal of the suppressed ß-adrenergic system. Indeed, ß-blockade1 8 9 10 or expression of an inhibitor for ßARK1, ßARKct,11 12 13 has been shown to decrease ßARK expression and increase ß1-AR density and ß-AR sensitivity to catecholamines in the failing myocardium.

Milano et al14 developed a transgenic (TG) strain in which the human wild-type (WT) ß2-AR gene was expressed under a mouse {alpha}-myosin heavy chain ({alpha}-MHC) promoter. This leads to an overexpression of the transgene with {approx}200-fold increase in ß2-AR density in the heart. TG mice show elevated cAMP levels and enhanced ventricular contractility and heart rate (HR) in the absence of agonist stimulation. This agonist-independent activation is explained by the ability of ß2-AR to spontaneously form the active conformation. Whereas the inactive conformer is by far the predominant one, with a nearly 200-fold increase in ß2-AR density, the number of "active" receptors would be substantially higher and sufficient to support a full physiological stimulation.14 15 This TG model provides a unique opportunity to study the role of the ß-adrenergic system in HF. In this model, the ß-adrenergic system is constitutively activated and would be expected to provide continued functional support under conditions of cardiac disorders. The aim of this study was to test whether enhanced ß-adrenergic activity and myocardial contractility might attenuate the development of HF after aortic stenosis.


*    Methods
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Mice and Transgene Screening
Parent TG mice (TG4) were generated at the Howard Hughes Medical Institute, Duke University Medical Center.14 Male TG mice were crossed with female F1 mice from the C57BL and SJL strains. The genomic DNA was extracted from tail biopsy, and expression of the transgene in offspring was detected by Southern blot hybridization using a 32P-labeled HincII fragment of the transgene construct.14 Both male and female animals, 3 to 6 months old, were used in this study.

Microsurgery
Mice were anesthetized (with a mixture of 8 mg/100 g ketamine, 2 mg/100 g xylazine, 0.6 mg/100 g atropine, and the pain reliever temgesic at 0.1 mg/100 g), intubated, and ventilated. Under a surgical microscope, a midline incision was made at the upper sternum. The aorta was dissected between the right innominate and the left carotid arteries and narrowed to a lumen size of 0.4 mm according to a method previously described.16 Control mice underwent similar surgery except for the narrowing of the aorta. The surgical procedures were approved by a local Animal Experimentation and Ethics Committee.

Functional Measurement
Cardiac function was assessed by a catheter placed into the right carotid artery (proximal to the stenotic site) and the left ventricle (LV). Mice were anesthetized with pentobarbitone (8 mg/100 g IP) and atropine (0.6 mg/100 g). When an animal was found to be sick (body weight loss, labored breath, motionless, etc), the dose of pentobarbitone was reduced to 3 to 4 mg/100 g. Mice were placed in the supine position on a heating pad, and the right main carotid artery was dissected. A microtipped transducer catheter (1.4F, Millar Instrument Co), with the frequency response flat to 10 kHz, was inserted into the artery and the LV. The aortic blood pressure, LV pressure, and maximal rate of increase or decay of LV pressure, dP/dtmax, or dP/dtmin were recorded. HR was derived from pulse signals.

Organ Weights
Mice were killed by an overdose of pentobarbitone. Before the heart was isolated, the chest was opened to determine whether pleural effusion was present. The heart was immersed in saline on ice. The LV, right ventricle (RV), and atria were separated and weighed. When an atrial organic thrombus was present, the weight of the thrombus was subtracted. The lungs and liver were weighed, and the tibial length was measured. The LV was then divided at the coronary plane at its ventricular equator. The upper halves were frozen in liquid nitrogen for mRNA determination, and the lower halves were fixed in 10% formalin solution for histological analysis.

Histology Analysis
Interstitial collagen content in the LV was determined by the method described previously.17 Fixed LVs were embedded in paraffin, and 5-µm sections were cut and stained with 0.1% picrosirius red (Polysciences Inc). Images gathered with a CCD video camera (Optimas, BioScan Inc) were digitized. The area stained was calculated as a percentage of the total area within a field. The sections were sampled in a systematic fashion, and 10 fields in each LV were analyzed. Fields containing vessels, patches of focal fibrosis, or artifacts were replaced by an adjacent field. Areas of myocardium exhibiting focal fibrosis were measured and presented as percentage of entire LV cross-sectional area.

Atrial Natriuretic Peptide mRNA
Total RNA was extracted from the LV as previously described18 and quantified. A 755-nucleotide EcoRI/SalI fragment of the rat atrial natriuretic peptide (ANP) cDNA was subcloned into pGEM-3Z for generation of cDNA probes.18 This cDNA fragment has >90% homology with the corresponding murine sequence. A riboprobe generated from a 177-nucleotide fragment of GAPDH cDNA was hybridized simultaneously as control. To quantify ANP mRNA levels, solution hybridization/nuclease protection assays were performed with 3 µg LV RNA as previously described,18 except that nuclease protection was performed by addition of 300 µL of digestion buffer containing RNase-T1 only (250 U, Boehringer Mannheim) to allow for slight mismatch between rat and mouse sequences. Nuclease-protected RNA hybrids were then detected and quantified by phosphorimage analysis (BAS system, Fuji) after electrophoresis on native polyacrylamide gels. The ratio of ANP/GAPDH mRNA in each individual sample was used.

Statistics
Results have been expressed as mean±SEM or as percentages. For parametric data, between-group comparison was made by ANOVA followed by unpaired Student’s t test. Fisher’s exact test was used to compare percentages between groups. The least-squares method was used for linear correlation and regression. All statistics were performed with the software program SigmaStat (Jandel Scientific).


*    Results
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Mortality and Incidence of Pathological Events
Five of 64 mice that were operated on were lost during surgery. All sham-operated mice (8 WT and 10 TG) survived to the time of experiment. In 13 WT and 28 TG mice with aortic stenosis, 8 mice (7 TG and 1 WT) died of HF and 1 (WT) of aortic rupture, judged by postmortem findings, during 3 to 55 days. These mice had massive pleural effusion and severe lung congestion (lung wet weight 469±41 mg, range 388 to 721 mg). Except for 1 TG mouse that died at day 3, all other mice developed severe hypertrophy (heart weight 229±19 mg, range 193 to 334; LV weight 162±15 mg, range 131 to 253 mg) and organic thrombus in the left atria.

We previously observed hypertrophy but no signs of HF in WT mice after aortic stenosis for 6 weeks (unpublished data). Thus, in this study, the time for functional examination was extended to 9 weeks. At the time of the experiment, 1 WT and 14 TG mice with aortic stenosis were so ill that they could not tolerate even a reduced dose of pentobarbitone. These mice also had reduced body weight postoperatively, presence of a chronic thrombus in the left atrium, pleural effusion, and enlarged LV cavity by visual inspection (Table 1DownDown). The incidences of pleural effusion and atrial thrombosis were higher in the TG than WT groups with aortic stenosis. Figure 1Down shows histological sections of the left atrium with organic thrombus and congested lungs from a TG mouse that died at the time of experiment.


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Table 1. Incidence of Pathological Events, Body Weight, and Normalized Organ Wet Weights in Sham-Operated Mice and Mice With Aortic Stenosis


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Table 1A. Continued



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Figure 1. Histological sections (hematoxylin-eosin stain) of lung and left atrium from TG mice with sham operation (A) or with aortic stenosis showing chronic pulmonary congestion (B) and an organic thrombus (arrow) in atrium (C). Bar=50 µm.

Functional Measurements
Before 14 TG mice were lost at the time of anesthesia, catheterization was done in the 7 remaining TG mice. These mice had less severe cardiac hypertrophy (heart weight 225±15 versus 266±9 mg, P<0.05) and lung congestion (lung wet weight 289±40 versus 388±16 mg, P<0.01) compared with the critically ill mice.

There was no significant difference in the arterial blood pressure between sham-operated WT and TG mice. Compared with sham-operated mice, proximal systolic arterial pressure increased significantly in mice with aortic stenosis, and there was no significant difference between TG and WT groups in the extent of systolic arterial pressure elevation (Table 2Down).


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Table 2. Arterial Blood Pressure and LV Function in Mice With Sham Operation or With Aortic Stenosis

In sham-operated mice, HR, LV dP/dtmax, and dP/dtmin were significantly higher in the TG than WT groups. In TG mice with aortic stenosis, dP/dtmax, dP/dtmin, and HR were significantly higher than in the WT counterparts (Table 2Up). However, TG and WT mice with aortic stenosis all showed a significant fall in dP/dtmax and dP/dtmin from respective control levels. TG mice tended to have more pronounced reduction in dP/dtmax than WT mice when expressed as percentages of respective sham-operated group means (-32±5% versus -16±6%, P=0.059). HR was similar between WT and TG groups with or without aortic stenosis but was significantly higher in TG than the respective WT groups (Table 2Up).

Body and Organ Weights
Although body weights were similar between the various groups at the time of surgery, body weights in TG mice with aortic stenosis were significantly lower than in other groups at the time of experiment (Table 1Up). WT and TG mice had significant increases in heart and lung weights 9 weeks after aortic stenosis. Weights of the LV, RV, and atria were all higher than those of sham-operated controls. TG mice with aortic stenosis had significantly greater weights of RV, atria, and lungs (all P<0.05). Marked cardiomegaly and LV dilatation were noticed at autopsy in TG mice with severe hypertrophy, atrial thrombosis, and lung congestion. TG mice with aortic stenosis had lower liver weight than either sham-operated control or WT mice with aortic stenosis (both P<0.05).

When results from WT and TG mice were analyzed together, lung wet weight correlated well with the whole-heart weight (r=0.807) and weights of the LV (r=0.714), RV (r=0.838), and atria (r=0.787, all P<0.001).

Interstitial Collagen Content
Collagen content in the interstitium of the LV was higher in the TG than WT sham-operated groups (0.82±0.15% versus 0.55±0.14%, n=8 to 10, P<0.05, Figure 2aDown and 2bDown) and remained unchanged after induction of hypertrophy in both TG and WT animals (0.80±0.15% and 0.40±0.07%, P=NS). In the LV from mice with aortic stenosis, however, there was apparent myocyte loss and replacement scarring (Figure 2cDown), as well as expansion of adventitial fibrous tissue (Figure 2dDown). The area of focal fibrosis in TG mice was significantly larger than in the WT group (P<0.05; WT, n=11; TG, n=17; Figure 2eDown).



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Figure 2. Representative sections of LV stained with picrosirius red showing collagenous trabeculae (arrows) separating bundles of myocytes (m) in sham-operated WT (a) and TG (b) mice, focal fibrosis in hypertrophied LV from a WT mouse (c), and perivascular collagenous adventitia infiltrating surrounding myocardium in hypertrophied LV from a TG mouse (d). e, Total area of focal fibrosis as percentage of entire cross-sectional area of hypertrophied LV was significantly greater in TG than WT groups (*P<0.05; TG, n=17; WT, n=11). Bar=25 µm.

ANP mRNA Expression
In WT mice, aortic stenosis increased ANP mRNA levels in the LV by 10-fold (Figure 3Down). In sham-operated TG mice, cardiac ß2-AR overexpression alone caused a 2-fold increase in basal ANP mRNA, in keeping with previous studies showing increased expression of immediate-early genes by ß-adrenergic stimulation.19 20 21 22 In TG mice that underwent aortic stenosis, expression of ANP was similarly upregulated to levels that were not significantly different from those measured in WT mice with aortic stenosis.



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Figure 3. A, Representative phosphorimage after simultaneous RNAse protection analysis of ANP and GAPDH mRNA. B, Quantitative analysis of changes in ANP mRNA of LV expressed relative to GAPDH mRNA. Bars represent mean±SEM of 6 individual mice per group. *P<0.01 for difference between TG and WT sham-operated groups; **P<0.001 vs respective sham-operated group.


*    Discussion
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*Discussion
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We hypothesised that an enhanced myocardial contractility caused by ß2-AR overexpression would alleviate the onset of HF after pressure overload. Contrary to our hypothesis, we observed deleterious consequences after aortic stenosis in TG mice overexpressing ß2-AR in the heart.

Relative to WT littermates, the TG mice had higher incidences of mortality and critical illness (both due to HF), pleural effusion, and atrial thrombosis. Furthermore, they developed more severe pulmonary congestion and focal fibrosis in the LV than WT mice. By week 9 after aortic stenosis, most TG mice developed congestive HF. In the mice suffering critical illness, the presence of chronic atrial thrombus and severe lung congestion indicated LV failure, leading to stasis in the left atrium, congestion in the pulmonary vascular bed, and subsequently RV hypertrophy. Under these conditions, the LV failed to hypertrophy further, suggesting that although the maximal extent of LV hypertrophy had been reached, the pump function could not be maintained in TG mice. Thus, ß2-AR overexpression leads to functional deterioration under conditions of pressure overload, whereas it has no effect on the extent of myocardial hypertrophy per se, as indicated by the similar heart weights and ANP expression between TG and WT mice 9 weeks after pressure overload.

In TG mice with aortic stenosis, HR levels remained higher than in WT mice. A high HR in the setting of an elevated afterload might be deleterious by increasing the energy expenditure in the heart. Development of severe hypertrophy would further limit the energy supply in the TG mouse heart. We observed a larger area of focal fibrosis in the hypertrophied LV of TG than WT mice. Previous studies showed that chronic catecholamine stimulation results in myocardial fibrosis,23 24 25 and this was prevented by ß-blockade.25 Similarly, fibrous changes in the LV myocardium have been reported in TG mice overexpressing Gs{alpha}.26 These two factors may contribute to the adverse consequences observed in the TG mice with pressure overload.

A similar deleterious effect of ß2-AR overexpression has been reported previously in a murine model of dilated cardiomyopathy and HF caused by disruption of muscle LIM protein (MLP).27 In this case, rather than restoring ventricular dysfunction, crossing the MLP-deficient mice with ß2-AR overexpressing mice significantly reduced survival.28 Thus, at least in two HF models, ß2-AR overexpression was deleterious. This is in keeping with the adverse outcomes from clinical trials that observed increased cardiovascular mortality and worsening of clinical symptoms in HF patients treated with ß-agonists or phosphodiesterase inhibitors.29 30 Furthermore, TG mice with cardiac overexpression of Gs{alpha} developed cardiomyopathy and HF at old age.26

Conversely, some studies have provided evidence that preventing ß-AR downregulation in failing hearts can be beneficial. ßARK1 is an enzyme involved in ß-AR downregulation and is closely linked to the functional state of ß-AR signaling and myocardial contractility.12 13 31 Expression of an inhibitor for ßARK1, ßARKct, in hypertrophied or MLP knockout myocardium improved cardiac function and prevented the development of HF.11 28 Thus, ßARKct expression and ß2-AR overexpression have very different effects on HF prognosis. In contrast to a marked and constant increase of HR in ß2-AR TG mice, expression of ßARKct does not increase basal HR, although overall, ventricular contractility is enhanced.13 Also, recent studies have pointed to an increased activity of Gi in mice with ß2-AR overexpression.32 Thus, there are a number of differences between the two TG models that might contribute to the different impacts on HF progression.28

In the TG line used, ß2-AR expression is controlled by {alpha}-MHC promoter.14 Before {alpha}-MHC is downregulated in hypertrophied and failing hearts,33 34 it is likely that the transgene is downregulated after the development of LV hypertrophy and failure. We recently found a 40% reduction in human ß2-AR mRNA level and receptor density in the LV of the TG mice with aortic stenosis for 8 weeks (unpublished data, 1999). However, such a reduced level of ß2-AR overexpression is still enough to maintain an activated ß-adrenergic system in these TG mice, indicated by higher levels of dP/dt and HR in the TG mice in which cardiac function could be measured, and to result in adverse outcomes.

In sham-operated TG mice, the interstitial collagen content of the LV was moderately higher than in WT controls. This has not been reported previously. We did not find cardiac hypertrophy in sham-operated TG mice. A preliminary study (A. Yatani, PhD, G.P. Szigeti, PhD, S. Liggett, MD, PhD, G.W. Dorn II, MD, PhD, unpublished observations, 1999) reported that hypertrophy, estimated by the patch-clamp technique (cell capacitance), may exist in ß2-AR TG mice without aortic banding. Thus, further studies are necessary to explore the phenotype of this TG model.

In conclusion, this study provides evidence that enhanced myocardial contractility caused by {approx}200-fold ß2-AR overexpression does not provide protection against pressure overload–induced HF. TG mice had a worse prognosis after aortic stenosis, suggesting that cardiac ß-adrenergic hyperactivity exacerbates the transition from hypertrophy to failure by pressure overload. This finding does not support the view that ß2-AR overexpression could be used as gene therapy,14 at least under the conditions of pressure overload. However, further studies are necessary to see whether this is also true for HF of different origin and whether ß2-AR overexpression at a low level is beneficial.


*    Acknowledgments
 
This work was supported by grants from Merck-Sharp and Dohme Research Foundation (Australia) and the Australia National Health and Medical Research Council. We are grateful to Dr R.J. Lefkowitz for providing the transgenic line, and to Elodie Percy, Sharon Harrison, Brian Jones, and the staff at Biological Research Unit for technical help.

Received March 29, 1999; revision received July 16, 1999; accepted July 20, 1999.


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up arrowResults
up arrowDiscussion
*References
 
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