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European Journal of Heart Failure 2003 5(2):131-136; doi:10.1016/S1388-9842(02)00243-X
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© 2002 European Society of Cardiology

Altered calcium transient and development of hypertrophy in β2-adrenoceptor overexpressing mice with and without pressure overload

Bettina Schwarza,*, Elodie Percyb, Xiao-Ming Gaob, Anthony M. Dartb, Gert Richardta and Xiao-Jun Dub

a Medizinische Klinik II, Universitätsklinikum Luebeck Ratzeburger Allee 160, 23538 Luebeck, Germany
b Baker Medical Research Institute Melbourne, Australia

* Corresponding author. Tel.: +49-451-500-2402; fax: +49-451-500-6279 E-mail address: katlab{at}medinf.mu-luebeck.de


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Transgenic (TG) mice with cardiac specific 200-fold overexpression of β2-adrenoceptors (β2-AR) have a facilitated development of heart failure following thoracic aortic constriction (TAC). We have studied the alterations of intracellular Ca2+ transients and myocyte size in wild-type (WT) and TG mice after TAC. Cardiomyocytes were isolated from mice 9 weeks after TAC or sham operation, and incubated with Fura 2/AM. The Ca2+ transients were determined by Spex dual wavelength Spectrometer during electrical stimulation. The cell size was also determined planimetrically. Cells of sham operated TG mice displayed higher systolic Ca2+ amplitude than respective WT group ({Delta}F340/F380 ratio: 1.05±0.08 vs. 0.63±0.05; P<0.01), a finding in keeping with enhanced ventricular contractility in the TG mice. However, hypertrophied and failing myocytes of TG animals showed a fall in Ca2+ transients from sham-operated control levels and there was no difference between TG and WT groups following TAC. In sham-operated groups, the cell size of TG mice was significantly bigger than in WT animals (3212±139 vs. 2605±162 µm2; P<0.05). The cell size increased to a similar extent in both groups after TAC (4715±216 vs. 5027±365 µm2, P=n.s.). In summary, hypertrophy of cardiomyocytes was present in β2-AR TG mice under baseline conditions. A further hypertrophy occurred during pressure overload to an extent similar to that in WT animals. However, the increased intracellular Ca2+ transient, seen in sham-operated TG mice, was no longer detectable following development of severe hypertrophy and heart failure. These findings provide explanation on the lack of hemodynamic benefit in β2-AR TG mice subjected to pressure overload.

Key Words: Intracellular calcium • β2-adrenoceptor • Transgenic mice • Hypertrophy • Heart failure • Pressure overload

Received July 26, 2002; Revised August 16, 2002; Accepted November 11, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
Alterations in the β-adrenergic signaling pathways under conditions of chronic heart failure are well recognized. The β1-adrenergic pathway undergoes a marked down-regulation and desensitization [1,2]. This involves a decrease in β1-adrenoceptor (β1-AR) mRNA and receptor internalization and uncoupling following β1-AR phosphorylation via β-AR kinase (βARK). Conversely, the β2-AR is not down-regulated leading to maintained β2-AR density in the hypertrophied and failing heart [1,3]. It has been proposed that a maintained or augmented β2-AR signaling pathway is beneficial in the failing heart by enhancing inotropism. Indeed, it was reported that adenoviral-mediated in vivo β2-AR gene delivery enhanced cardiac function [4]. Likewise, a transgenic (TG) strain of mice with a 200-fold overexpression of β2-AR had significantly enhanced adenyl cyclase activity and ventricular contractility under baseline conditions, suggesting an activated β2-adrenergic signaling due to agonist-independent mechanism [5,6]. These results suggest that an upregulated β2-adrenergic pathway might provide inotropic support to improve myocardial performance in chronic heart failure.

We recently investigated the clinical and hemodynamic changes in β2-AR overexpressing mice after chronic pressure overload. In contrast to our expectations, the TG animals had a facilitated and exacerbated development of heart failure, with premature mortality and clinical signs of heart failure such as pleural effusion, atrial thrombus and lung congestion. Ventricular contractility was suppressed more in TG than in respective wild-type (WT) mice with pressure overload [7,8]. Since impaired Ca2+ handling is implicated as a fundamental mechanism for myocardial dysfunction [9,10], the present study was designed to investigate the intracellular Ca2+ transients and cell size, to gain insight into the relationship between activated β2-AR signalling and heart failure.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
2.1. Animals
Parent TG mice (TG4) with a 200-fold overexpression of human β2-AR were generated at the Howard Hughes Medical Institute, Duke University Medical Center, North Carolina [5]. Male TG4 mice were crossed with female F1 mice from C57BL and SJL strains. Genomic DNA was extracted from mouse tail biopsy and the transgene in offspring was detected by slot blot hybridization, using a 32P-labeled Hinc II fragment of the transgene construct. Both male and female animals of TG and WT littermates, 3–4 months of age, were used in this study.

2.2. Microsurgery
The surgical procedures were approved by the local Animal Experimentation and Ethics Committee. Mice were anaesthetized with a mixture of ketamine (8 mg/100 g), xylazine (2 mg/100 g), atropine (0.06 mg/100 g) and a pain reliever temgesic (0.1 mg/100 g). Animals were intubated and ventilated. With the aid of a surgical microscope, a midline incision was made at the upper sternum and the aorta was dissected between the right innominate and the left carotid arteries. The aorta was then constricted by 60–70% to a lumen size of 0.4 mm following the method of Rockman et al. [11]. Sham-operated mice were subjected to the same surgery except for the banding of the aorta. The mortality during the first 24 h after surgery was 16%. Animals were inspected daily and used 9 weeks after surgery.

2.3. Isolation of cardiomyocytes
Nine weeks after thoracic aortic constriction (TAC) or sham operation (SH), mice were injected with heparin (5000 U/kg i.p.) and killed after 30 min. The chest was opened and the heart was quickly removed and placed in ice-cold, nominally Ca2+-free solution. The solution contained (in mM) 100 NaCl, 5.4 KCl, 3.5 MgSO4, 0.05 pyruvate, 20 NaHCO3, 11 glucose, 20 HEPES, 23.5 glutamate, 4.87 sodium acetate, 0.1 EDTA, 10 2,3-butanedione monoxime, 5 creatine and 30 taurine. Insulin (100 IU/ml) and phenol red were added and pH was adjusted with NaOH to 7.25. The buffer was gassed with 95% O2/5% CO2 and warmed to 37 °C. The aorta was cannulated and the heart retrogradly perfused with Ca2+-free buffer at a flow rate of 2.2 ml/min. After a 10-min equilibration period, collagenase was added to the perfusion solution at 2 mg/ml and the heart was digested for 30 min. The heart was then removed from the cannula, transferred into a culture dish and minced. The tissue was triturated gently until the whole tissue was dissolved. The supernatant containing myocytes was filtered through a 200 µm mesh filter. The cells were reintroduced stepwise to Ca2+ up to a concentration of 1.8 mM/l. Finally the cells were resuspended in a culture medium (DMEM) and incubated for 1 h.

2.4. Calcium transients
Fresh isolated cells were incubated for 30 min with 1 µM Fura 2/AM (Calbiochem, La Jolla, USA) at 37 °C. After the loading period the cells were washed to remove non-incorporated Fura 2/AM and then mounted on a thermostatic chamber of a Nikon inverse microscope connected with the Spex dual wavelength Spectrometer (Spex Instruments Inc.) according to the method described previously in detail [12]. Ca2+ measurement was performed using the HEPES buffered Tyrode's buffer containing Ca2+ at 1.8 mM/l. Cells were field stimulated with a single train of impulses at 7 mV for 10 ms, delivered by a pair of platinum electrodes linked with a Grass S88 stimulator. Excitation wavelengths were 340 and 380 nm, respectively, and the fluorescence emission was detected at 505 nm and expressed as the ratio of the two excitation wavelengths (F340/F380). The amplitude of the Ca2+ transient at systole was calculated by subtraction of the baseline F340/F380 ratio from the peak values.

2.5. Determination of cell size
Cells were placed on a light microscope with CCD video camera (Optimas, BioScan, Edmonds, USA). Images were analyzed digitally using Optimas 6.5 program. Areas of 30 cells per heart (four to six hearts in each group) were quantitated by planimetric measurement and the average was calculated from all cells of one group.

2.6. Statistics
Results are expressed as percentages or mean±S.E.M. The P-values were determined either by Fisher's exact test for percentage differences or by one- or two-way analysis of variance followed by unpaired Student's t-test for parametric data using the Sigma Stat statistical package. A P-value less than 5% was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
Operated animals were used 9 weeks after the surgery. All sham-operated TG (n=7) and WT (n=6) mice survived to the time of the experiments and did not have any gross morphological abnormalities. Ten TG and seven WT mice survived 24 h after TAC. The rate of premature death, mostly due to severe left heart failure, was higher in TG than in respective sham-operated groups (Table 1). During isolation of the heart we inspected for clinical evidence of heart failure [7]. All surviving TG mice with TAC, developed pleural effusion and chronic thrombus in the left atrium and the incidence of these events was higher than in the WT mice with TAC, but this difference was not statistically significant due to a smaller group size. These findings are consistent with our previous reports [7,8] indicating more pronounced heart failure in TG mice after TAC.


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  		Table 1 Post-operative mortality and incidence of pathological events in transgenic (TG) and wild-type (WT) animals 9 weeks after thoracic aortic constriction (TAC) or sham operation (SH)

 
3.1. Myocyte size
The size of cardiomyocytes from SH and TAC mice was quantitated. The TG mice with sham-operation had 19% bigger cell size than that in the WT animals (2605±162 vs. 3212±139 µm2, P<0.05, Fig. 1a,b). This finding is unexpected since we previously found that the left ventricular weight was not different to that in WT mice [7,8]. In response to chronic pressure overload, the cell size increased markedly in hearts of both WT and TG mice (P<0.01 vs. respective SH groups) and there was no significant difference between WT and TG groups in the extent of hypertrophy (Fig. 1a,b). The extent of cell enlargement was in proportion to an approximately 70% increase in left ventricular weight, 8–9 weeks after TAC [7,8].


Figure 1
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  		Fig. 1 (A) Representative myocytes from SH and TAC mice. (B) Planimetric measured cell size of isolated cardiomyocytes from wild-type (WT) and β2-overexpressing transgenic (TG) mice 9 weeks after sham surgery (SH) or thoracic aortic constriction (TAC). Thirty cells from each heart were measured and each group included four to six hearts. *P<0.05; **P<0.01.

 
3.2. Intracellular Ca2+ transient
To characterize the hypercontractility of TG mouse hearts at the cellular level, we studied the Ca2+ transient in myocytes from SH and TAC mice. Ca2+ signals were measured from seven cells per heart and each group comprised three~seven hearts. The Ca2+ amplitude at systole was 45% higher in sham-operated TG animals compared to the respective WT group ({Delta} fluorescence ratio 1.05±0.08 vs. 0.63±0.05; P<0.01, Fig. 2a,b), indicating a greater rise in intracellular Ca2+ at the time of membrane depolarization. After 9 weeks of TAC, the Ca2+ amplitude in hypertrophied cells from TG animals was reduced to the level that was no longer different from the respective WT group (0.80±0.10 vs. 0.72±0.05; P=n.s., Fig. 2b). This finding is in keeping with our previous studies showing that the enhanced inotropism in the β2–AR overexpressing animals was largely lost under conditions of chronic aortic constriction [7].


Figure 2
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  		Fig. 2 (a) Representative calcium transients ({Delta} fluorescence ratio F340/F380) from sham-operated (SH) wild-type (WT) and transgenic (TG) animals. (b) Calcium transient evoked by electrical stimulation in cardiomyocytes from wild-type (WT) and transgenic (TG) mice overexpressing β2-AR after sham operation (SH) or thoracic aortic constriction (TAC) for 9 weeks. Isolated myocytes were loaded with the Ca2+ sensitive fluorescence dye Fura 2 at 1 µmol/l for 30 min (37 °C). Cells were then electrically stimulated to contract and were alternately illuminated at 340 and 380 nm lights. Emission of Fura 2 was measured at 505 nm. The ratio of fluorescence emission from the two illuminating wavelengths was used to follow the intracellular Ca2+ transient. {Delta}Fura 2 ratio means difference between F340/F380 ratios at peak systole and basal diastole. Data are means±S.E.M. from 14 to 20 cells. *P<0.05.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
In the hypertrophied and failing heart, β-adrenergic signaling, especially the β1-AR mediated pathway, undergoes profound down-regulation which is implicated as an important mechanism for suppressed myocardial performance under these conditions [1,2]. In contrast, β2-AR density is maintained, although receptor uncoupling occurs to some extent.

Our study using a transgenic model illuminates the cellular effects of β2-AR activation regarding the morphology and Ca2+ transient of cardiomyocytes. A marked increase in the amplitude of intracellular Ca2+ at systole was observed in myocytes of sham-operated TG mice. It is very likely that such elevated systolic Ca2+ signal is responsible for enhanced ventricular contractility reported in this strain both in vitro and in vivo [5,6,13]. Increased Ca2+ levels at systole might be due to a greater amount of Ca2+ influx and/or Ca2+ release from the sarcoplasmic reticulum by the activated β-adrenergic pathway. Several groups have recently found that in cardiomyocytes from the β2-AR TG mice, the L-type Ca2+ channel current (ICa) is similar [13] or even slightly lower than in WT controls [14,15]. Enhanced ICa in TG4 mice occurs only after pre-treatment with pertussis toxin to inactivate Gi/o proteins [13]. Thus, a higher level of Ca2+ during membrane depolarization, seen in the present study, is due to enhanced release of Ca2+ from the sarcoplasmic reticulum rather than increased influx. β-Adrenergic activation is known to enhance sarcoplasmic Ca2+-ATPase (SERCA) function through disinhibition following phospholamban phosphorylation by protein kinase A [9].

At cellular level such enhanced Ca2+ transient is associated with increased cell size indicating myocardial hypertrophy under baseline conditions. This is apparently due to the maximally activated β2-adrenergic system. In the TG4 strain, expression of some hypertrophy-associated genes was increased in TG mice at young age without TAC [7], and severe fibrotic cardiomyopathy and heart failure were observed between 9 and 15 months of age with a poor survival [16]. Although the extent of the hypertrophy was moderate in these sham-operated TG mice at 4–7 months of age, this finding implies that the onset of cardiac abnormalities is earlier than previously observed. Interestingly, wet weights of the heart and left ventricle were similar in sham-operated TG and WT mice [7,8]. The increased myocyte size without change in heart weight suggests the loss of cardiac cells. Indeed, loss of cardiomyocytes becomes dramatic in this strain at older age [16].

The mechanism leading to cell hypertrophy remains undefined. Since this strain possesses a markedly enhanced ventricular contractility, the mechanical stress on the myocardium would be elevated considerably. It is known that biomechanical stress can initiate hypertrophic growth via activation of mechanical sensitive cation channels or ion exchangers such as Na/H exchanger [17]. Schlüter et al. [18] showed a pro-hypertrophic effect of β2-AR activation in the presence of transforming growth factor-β (TGF-β). Further studies are required to address the mechanisms of hypertrophy and the possibility of cell loss in the β2-AR TG strains [15,16].

Following TAC, β2-AR TG mice experienced more rapid functional deterioration with no difference in the extent of cardiac hypertrophy [7,8]. In this study, both WT and TG mice responded to pressure overload with a remarkable increase in myocyte size and, after aortic banding, the previous difference in cell size between TG and WT mice was lost. We were able to confirm our previous finding of an accelerated development of heart failure. This became apparent with a higher mortality and clinical events like pleural effusion and atrial thrombus. Interestingly, Ca2+ transient decreased in the hypertrophied and failing TG hearts from the sham-operated control levels. This finding provides one explanation at the cellular level for the failure by β2-AR overexpression in preventing the onset of heart failure under conditions of pressure overload [7,8]. Although the finding of a reduced Ca2+ transient is of interest, our data do not allow us to conclude whether this change is a primary or secondary phenomenon. However, it is clear that in the hypertrophied myocardium of the β2-AR TG mice, β2-AR activation failed to keep Ca2+ transient higher than in WT. This is associated with the loss of functional compensation and a higher incidence of heart failure.

The cellular response to β2-AR overexpression is known to depend on the copy number of the transgene products. Liggett and co-workers [15] reported that very high levels of β2-AR overexpression result in cardiomyopathy, whereas in animals with moderate and low expression levels of β2-AR the enhanced adrenergic pathway did not result in deleterious consequences in function and morphology. Furthermore, overexpression of β2-AR at a low level by crossbreeding rescued dysfunction and cardiomyopathy in mice expressing G{alpha}q in the heart. In contrast, high levels of β2-AR overexpression worsened the cardiac performance [19]. Recent studies have also shown that 5–20 fold overexpression of β2-AR by adenoviral gene transfection improved ventricular function in the failing rabbit heart [2].

In conclusion, high levels of β2-AR overexpression significantly enhanced Ca2+ transient in adult murine cardiomyocytes. Under conditions of chronic pressure overload, however, the cellular phenotype deteriorated to hypertrophied and failing myocytes and this is associated with severe heart failure in the β2-AR TG mice. Moreover, a 200-fold overexpression of β2-AR per se induces myocyte hypertrophy which proceeds the development of cardiomyopathy and heart failure observed in this strain [16].


   Acknowledgements
 
We are grateful to Dr Robert Lefkowitz for providing the transgenic line and to Drs Peter Little and Craig Nylon for their kind help. We thank the staff at Biological Research Unit, Baker Institute for their technical assistance. This study was supported by the National Health and Medical Research Council of Australia and the Deutsche Forschungsgesellschaft.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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