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European Journal of Heart Failure 2007 9(12):1156-1162; doi:10.1016/j.ejheart.2007.10.007
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© 2007 European Society of Cardiology

Parathyroid hormone-related protein (PTHrP) signal cascade modulates myocardial dysfunction in the pressure overloaded heart

Rainer Meyera, Rolf Schreckenbergb, Frank Kretschmera, Anne Bittiga, Charlotte Conzelmannb, Christian Grohéc and Klaus-Dieter Schlüterb,*

a Physiologisches Institut II, Universitätsklinikum Bonn Germany
b Justus-Liebig-Universität, Physiologisches Institut Aulweg 129, D-35392 Giessen, Germany
c Medizinische Universitäts-Poliklinik Universitätsklinikum Bonn, Germany

* Corresponding author. Tel.: +49 641 99 47 212; fax: +49 641 99 47 219. Klaus-Dieter.Schlueter{at}physiologie.med.uni-giessen.de


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: Pressure overload induces the cardiac expression of parathyroid hormone-related protein (PTHrP). Plasma levels are elevated in patients with heart disease. It is unknown whether this represents an epiphenomenon or suggests involvement in hypertrophy.

Aim: To identify a potential role of PTHrP in pressure induced hypertrophy and heart failure.

Methods and results: Pressure load was produced via thoracic aortic constriction (TAC) and application of a PTHrP antagonist (PTHrP(7–34)) via osmotic minipumps in mice. Main findings were confirmed in vitro by exposing isolated adult ventricular mice cardiomyocytes to PTHrP(1–34) (100 nmol/l). TAC treated animals developed myocardial hypertrophy within 2 weeks. The heart weight to body weight ratio increased from 5.02±0.14 mg/g (sham/vehicle) and 5.16±0.19 mg/g (sham/antagonist) to 6.59±0.85 mg/g (TAC/vehicle) and 7.07±0.80 mg/g (TAC/antagonist) (each n=6–8; p<0.05 for TAC vs. sham; not significantly different between TAC groups). In parallel, the expression of atrial natriuretic factor increased. Cardiac dysfunction (+dP/dt, –dP/dt), however, was significantly lower in TAC mice receiving the antagonist, and SERCA2 expression was higher. Isolated cardiomyocytes exposed to PTHrP(1–34) developed reduced cell shortening. This reduction in cell function was abolished in the co-presence of the antagonist.

Conclusion: PTHrP contributes to the progression of cardiac dysfunction in the pressure overloaded heart.

Key Words: SERCA • Diastolic function • Myocardial hypertrophy

Received July 6, 2007; Revised August 22, 2007; Accepted October 18, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Parathyroid hormone-related protein (PTHrP) was initially identified as a factor responsible for humoral hypercalcaemia of malignancy [1-3]. It is now well established that PTHrP is constantly expressed in multiple non-malignant cells. Within the cardiovascular system, endothelial cells, smooth muscle cells, and atrial myocytes express PTHrP. Since PTHrP plasma levels are normally low, PTHrP is thought to act mainly via paracrine, autocrine, or intracrine pathways. Smooth muscle cells and cardiomyocytes have been identified as cardiovascular target cells for PTHrP, on which the peptide acts via binding to and stimulation of the classical PTH/PTHrP receptor. Expression of this receptor on endothelial cells is still a matter of debate. However, PTHrP has been shown to act on endothelial cells [4]. In addition to the classical PTH/PTHrP receptor, another receptor subtype has been described with a different cross reactivity to members of the PTH family [5]. Moreover, these two receptors have been shown to influence each other [6].

In a previous study, we investigated the ventricular expression of PTHrP in relation to hypertension related hypertrophy [7]. It was found that induction of ventricular PTHrP expression is a very early feature of ventricular adaptation to pressure overload, stimulated before the induction of hypertrophy-associated genes like the atrial natriuretic peptide (ANP). The induction of PTHrP is rapid but transient. It was also found that sustained pressure overload to the heart leads to an up-regulation of TGF-β1. This factor depresses ventricular expression of PTHrP [7]. Evidence for a pressure-dependent regulation of ventricular PTHrP expression also comes from our previous findings, that application of angiotensin converting enzyme (ACE)-inhibitors to spontaneously hypertensive rats reduces PTHrP expression, irrespective of their anti-hypertrophic action [8]. Finally, PTHrP can be released from isolated coronary endothelial cells in a mechanosensitive way [9]. Further evidence of the direct participation of PTHrP in pressure adaptation of the heart comes from work on isolated ventricular cardiomyocytes. It was found that PTHrP, via its protein kinase C (PKC)-activating domain located at position 107-111, increases protein synthesis of cardiomyocytes, thereby increasing the ratio of protein synthesis to protein degradation and contributing to myocardial hypertrophy [10].

All the aforementioned findings led us to speculate that PTHrP is directly involved in the pressure-dependent adaptations of the heart. However, a causal relationship between increased ventricular PTHrP expression and changes in ventricular function remains to be established. This study was therefore conducted to either prove or disprove such a relationship. In order to demonstrate the involvement of PTHrP in the adaptation of pressure overload we used a well established model of pressure overload, namely thoracic aortic constriction (TAC), and blocked the activity of PTHrP by application of a PTHrP receptor antagonist (PTHrP-AG), PTHrP(7-34), via osmotic minipumps. Cardiac hypertrophy, expressed as heart weight to body weight, cardiac haemodynamics, determined via left heart catheterization in anaesthetised mice, and ventricular expression of hypertrophy-associated genes, determined by real time RT-PCR, were analyzed after 14 days. The conclusion of these findings was confirmed in vitro on age matched isolated cardiomyocytes from mice.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Experimental model and haemodynamic measurements
Experiments were performed on adult male C57BL/6 mice at an average age of 51±2 days and an average weight of 20.65±1.66 g (Charles River, Sulzfeld, Germany). Animals were kept in individually ventilated cages in a room with a 12 h light/dark cycle and maintained at a temperature of 20±1 °C, with free access to standard mouse chow and water. Cardiac hypertrophy was induced by transverse aortic constriction (TAC), as described in detail in [11]. Briefly, the mice were anesthetized with isoflurane (2.5% vol/vol; Forene®, Abott GmbH, Wiesbaden, Germany), intubated and ventilated with the suitable parameters. After opening the thorax a suture was passed underneath the aorta and tied down on a 27G needle to achieve a standardised decreased diameter of the aorta. Sham operated animals were treated in the same way without ligation of the suture. Both groups, TAC and sham surgery, received either vehicle or PTHrP(7-34), a PTH/PTHrP receptor antagonist. Vehicle or PTHrP(7-34) was administered via implanted osmotic minipumps (Alzet 1002, Alzet Osmotic Pumps, Cupertino, CA, USA) which released their contents in a controlled way over the next 14 days. The pumps were filled with either 50 µg of the antagonist in 100 µl isotonic NaCl solution which was released at a rate of 125 ng/h or vehicle The animals were housed in individual cages to avoid injuries along the suture near the implant.

Animals were evaluated after 14 days and left ventricular function was determined under anaesthesia. Preparation was performed under isoflurane (2.5% vol/vol), and recordings under isoflurane 1% (vol/vol). Haemodynamic parameters were recorded with a Millar pressure-transducer catheter (Millar Instruments, Houston, TX, USA) connected to a computerized data acquisition system (Power Lab., ADI Instruments, Melbourne, Australia) as described previously (11). The Millar-catheter was introduced into the right carotid artery and then moved forward to a position 4 mm in front of the aortic valve to record blood pressure. Finally, it was advanced into the left ventricle to assess ventricular function. After the haemodynamic measurements the animals were sacrificed by exsanguination, the hearts were excised and all external fluids were completely removed before weighing. The hearts were then frozen prior to further analysis.

The animals were handled according to the principles of laboratory animal care (NIH publication No. 86-23, revised 1985) and to the animal protection law stated in the German Civil Code. The experiments were approved by the district government.

2.2. Quantification of mRNA expression
The hearts were homogenized and RNA was extracted according to the manufacturer's protocol to obtain total cellular RNA as described previously [8]. Aliquots (1 µg) were used for real-time polymerase chain reactions (PCRs) using the I-cycler (Biorad, Germany) and Syber-green as the fluorescence signal. The expression of transforming growth factor (TGF)-β1, ornithine decarboxylase (ODC), atrial natriuretic peptide (ANP), and SR-Ca2+-ATPase (SERCA)2A were normalized to β-actin, as a housekeeping gene used for loading control. The primers used in this study have been reported previously [7-9].

2.3. Cell isolation and determination of cell shortening
Ventricular cardiomyocytes were isolated from the mice as described before in greater detail [12]. The cells were suspended in basal culture medium and plated on 60 mm culture dishes. The culture dishes had been pre-incubated overnight with laminin (1 g/ml) dissolved in water. The basal culture medium (CCT) was modified medium 199 including Earl's salts, 2 mmol/l carnitine, 5 mmol/l creatine, and 5 mmol/l taurine. To prevent contamination, 100 IU/ml penicillin and 100 µg/ml streptomycin were added. In addition, 10 µmol/l cytosine-β-D-arabinofuranoside was added to inhibit growth of non-myocytes.

Four hours after plating, cultures were washed twice with CCT medium. As a result of the medium change, damaged cells were removed resulting in cultures of about 90% quiescent rod-shaped cells. Cells were cultured in the presence of PTHrP, PTHrP antagonist, or vehicle for 24 h.

Cell shortening was determined as described before in greater detail [13]. Briefly, cells were assessed at the time periods specified in the result section. All cell-shortening experiments were performed at room temperature. Only rod shaped cells that contracted regularly were used for quantification. Cell length was analyzed using a line-camera. Cells were stimulated at 2 Hz for 1 min and every 15 s cell shortening was measured. The median of these 4 shortenings per cell was used as the average cell shortening of the individual cell. Data recording and calculations were performed via the cell edge detection system and supplementary soft ware (Scientic Instruments, Heidelberg, Germany).

2.4. Determination of plasma PTHrP
At the end of the experiments, hearts were removed and blood samples were taken. The plasma from these samples was analyzed for PTHrP as described before [9]. Briefly, plasma samples were dissolved with water, mixed with Laemmli buffer, and loaded on a SDS gel. PTHrP was visualized by immunoblotting using an anti-PTHrP IgG directed against amino acids 56-83. Blots were quantified densitometrically.

2.5. Statistics
Data are presented as means±S.E. from n experiments. Where more than two groups were compared, analysis of variance was performed, using a Bonferroni post hoc analysis. A p value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Effect of PTHrP antagonism on myocardial hypertrophy
In the first set of experiments, mice were exposed to pressure overload by thoracic aortic constriction (TAC) or sham surgery and received the PTHrP antagonist or vehicle thereafter for the next 14 days. The mice used in this study did not differ in regard to body weight (Table 1). After 14 days, there was a slight loss of body weight in both TAC groups while the sham groups slightly increased their body weights. However, no significant differences were observed. Increased levels of PTHrP could be detected in the plasma from TAC animals compared to sham operated animals at the end of the experimental period (Fig. 1). On average, plasma PTHrP was elevated by 2.7±0.6-fold in TAC treated animals which received the antagonist and 2.3±0.3-fold in TAC animals which received vehicle compared to sham operated animals (p<0.05 vs. sham group). There was no significant difference between the two TAC groups. In both TAC groups left ventricular weights and heart weights were significantly increased compared to sham operated animals (Table 1). This was also true when heart weights were normalized to either body weight or tibia length (Table 1). There were no differences between sham animals or TAC mice receiving either antagonist or vehicle.


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  		Table 1 Influence of PTHrP antagonism (AG) on TAC induced hypertrophy

 


Figure 01
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  		Fig. 1 Representative immunoblot indicating PTHrP immunoreactivity in the plasma from mice with thoracic aortic constriction receiving either vehicle (TAC), or PTHrP antagonism (TAC+AG), or from sham operated animals. The band represents the main band in the plasma of approximately 50 kD.

 
The results on gross characterization of myocardial hypertrophy were confirmed on the basis of hypertrophy-associated gene transcription. In both TAC groups, ANP mRNA expression was increased compared to sham operated animals, but there was no difference between TAC groups (Table 2). Similarly, the expression of TGF-β1 mRNA was increased in both TAC groups. ODC mRNA expression was strongly increased in both TAC groups with no differences between the mice receiving the antagonist or not (Table 2). However, in the antagonist treated groups the expression of SERCA2A was significantly increased, irrespective of the TAC treatment (Table 2).


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  		Table 2 Influence of PTHrP antagonism (AG) on TAC induced hypertrophy-dependent gene regulation

 
3.2. Characterization of left ventricular function
In contrast to markers of myocardial hypertrophy, there were significant differences in left ventricular function between antagonist treated and non-treated animals. Left ventricular systolic pressure was higher in TAC banded animals compared to sham animals, although the differences did not reach significance (Table 3). Left ventricular diastolic pressure was increased in both TAC groups, indicating the onset of heart failure (Table 3). There was a trend for increased heart rates in both TAC groups, which was significant for the antagonist treated group (Table 3). In TAC animals receiving the antagonist, the first positive derivative of left ventricular pressure (dP/dtmax) was significantly higher than the values in TAC mice receiving vehicle (Table 3). Similarly, the first positive derivative of left ventricular pressure (dP/dtmax) was significantly higher in antagonist treated sham animals compared to vehicle-treated sham animals (Table 3). Relaxation properties, determined as the first negative derivative of left ventricular pressure (dP/dtmin), were significantly reduced in TAC animals receiving vehicle. They were significantly increased in animals receiving the antagonist, although the relaxation properties of sham animals were not totally restored (Table 3). There were no differences in relaxation properties between vehicle and antagonist in the sham groups (Table 3).


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  		Table 3 Effect of PTHrP antagonism (AG) on TAC induced changes in cardiac performance

 
3.3. Effect of PTHrP on cell shortening
The aforementioned results suggest that PTHrP contributes to the loss of function in the pressure overload model. This causal relationship was proven on a single cell basis. Isolated ventricular cardiomyocytes from mice were exposed to either PTHrP(1-34) or PTHrP(7-34), the antagonist used in the in vivo experiments, to determine whether chronic (24 h) exposure of cardiomyocytes to PTHrP alters cellular function. Fig. 2 shows representative single cell recordings. Cells exposed to PTHrP developed an approximately 29% decrease in cell shortening, compared to untreated control cells (Table 4). This reduction was abolished in cultures co-treated with the antagonist. However, even the antagonist alone increased cell shortening. Similar concerns hold for the maximal contraction and maximal relaxation velocity as well (Table 4).


Figure 02
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  		Fig. 2 Representative recordings of cell shortenings of isolated cardiomyocytes treated with PTHrP peptides as indicated for 24 h and paced at 2 Hz thereafter. Cell shortenings are normalized to diastolic cell lengths.

 


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  		Table 4 Effect of PTHrP and its antagonist on the contractile responsiveness of isolated cardiomyocytes

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
4.1. Main findings
The present study was designed to evaluate the functional consequences of pressure-dependent increased myocardial PTHrP expression. The results suggest that PTHrP, via stimulating PTHrP receptors by its N-terminal domain, contributes to the development of cardiac dysfunction, without having any influence on hypertrophic growth. The conclusion from the study is based on our finding that PTHrP antagonism in vivo does not alter any signs of hypertrophic growth or hypertrophy-associated gene transcription. However, it significantly reduced the loss of ventricular function found in this model. The conclusion is confirmed by the in vitro finding, that synthetic PTHrP(1-34) induces a loss of cell function that could be blocked by co-application of the antagonist used in the in vivo model.

4.1.1. PTHrP and myocardial hypertrophy
The question whether PTH/PTHrP receptors contribute to the development of myocardial hypertrophy has been considered in regard to the clinical finding that patients with hyperparathyroidism often develop cardiac complications [14]. Myocardial hypertrophy is one of the most prominent findings in these patients [15]. PTH can increase protein synthesis in cardiomyocytes via its PKC-activating domain and therefore may play a role in such settings [16]. However, PTHrP does not represent the PKC-activating domain and therefore does not increase protein synthesis directly [17]. On the other hand, factors contributing to myocardial hypertrophy, such as angiotensin II or norepinephrine, increase PTHrP expression in smooth muscle cells [18,19]. In the present study, in which the activity of the N-terminal domain of PTHrP was antagonized, no evidence of the involvement of PTHrP in the growth adaptation of the heart to pressure overload was found. In the N-terminal part of PTHrP no PKC-activating domain is represented. A PKC-activating domain is represented at amino acids 107-111 [20]. As PKC-activation is sufficient to increase hypertrophic growth in cardiomyocytes, the results of this study do not rule out the possibility that PTHrP is involved in the hypertrophic growth response. This may still occur via its PKC-activating domain represented at position 107-111. On the other hand, the results rule out involvement of the N-terminal domain of PTHrP in this process.

4.2. Effect of PTHrP on cellular function
The acute effects of PTH and PTHrP on cardiomyocytes have been established in recent years. The data have shown that either PTH or PTHrP can modify contractile responsiveness via cAMP-dependent protein kinase (PKA)-independent [16,21] and PKA-dependent pathways [22,23]. Among the intracellular signal transduction pathways involved in these signalling steps, a modification of calcium channel activity may need to be taken into consideration [21-23]. The functional effects of long term exposure of cardiomyocytes to PTH/PTHrP have not been investigated. The data we obtained in vivo and in vitro suggest that chronic stimulation of PTH/PTHrP receptors by the N-terminal part of PTHrP reduces cellular function. The demonstration of such effects in vivo and in vitro at least suggests that the in vivo effect found in the TAC animals treated with the antagonist represents an inhibitory effect of the PTHrP antagonist. In a previous study, a rapid but transient up-regulation of myocardial PTHrP expression was found [7]. This suggests that the observed effect of PTHrP antagonism on left ventricular function is related to PTHrP-dependent adaptations to pressure overload. It is in line with these suggestions, that synthetic and biologically active PTHrP induces such changes in vitro within 24 h. This reflects exactly the time course in which PTHrP is induced in vivo in the case of chronic pressure overload (7). Under clinical conditions, serum PTHrP concentration correlates with the degree of cardiac dysfunction of patients with chronic heart failure [24]. As expected from these studies, serum PTHrP was also elevated in the chronic pressure overload mouse model used here. The experimental study described here suggests a mechanistic basis for the clinical observation. If one assumes that PTH might act in a similar way via a common PTH/PTHrP receptor, one can also take into consideration clinical studies that analysed haemodynamic function in patients with hyperparathyroidism. These patients developed signs of diastolic dysfunction even after parathyroidectomy and normalization of PTH values [25,26]. Again, the experimental study performed here might indicate a mechanistic basis for such dysfunction. Whether, PTHrP is responsible for cardiac complications in patients with PTHrP-producing tumours remains to be evaluated but is also possible.

4.3. Effect of PTHrP on hypertrophy-associated gene regulation
Pressure overload is characterized by modifications of specific gene expression, converting a primary adaptive form of hypertrophy into a mal-adaptive form of hypertrophy. One of the key players involved in the transition of hypertrophy to heart failure is TGF-β1. In the experiments performed in this study we could basically confirm this, although not as a causal relationship. The hearts used in this study developed signs of heart failure, i.e. increased diastolic left ventricular pressure, and exhibited indeed increased myocardial TGF-β1 mRNA levels. In previous studies with transgenic mice overexpressing TGF-β1 or spontaneously hypertensive rats, a corresponding increase in ODC mRNA expression was found. An increased myocardial ODC mRNA expression normally goes along with altered β-adrenoceptor signalling (reviewed in Ref. [27]). In the mouse heart, β-adrenoceptor stimulation plays a prominent role [28]. This may be more important in mice than in rats [28]. The most remarkable observation of the mRNA analysis performed in our study is the increased expression of SERCA2A in antagonist treated mice. This gives a causal link to the observed improvement of diastolic function, as found for –dP/dt and increases in relaxation velocity. As shown previously, increased SERCA expression is sufficient to antagonize cardiomyocyte-specific loss of function [29].

4.3.1. PTHrP(7-34) antagonism
Initially, the PTHrP receptor antagonist used in this study was used as a classical PTH/PTHrP receptor antagonist. Due to the fact that it lacks the first 6 amino acids, it is unable to activate cAMP/PKA-dependent pathways [30]. As PTHrP does not activate PKC via amino acids 28-32 in rat cardiomyocytes we considered this antagonist as suitable for this study. However, the outcome of the study showed that the antagonist is not an inert peptide. It increased SERCA expression even in sham mice, and it improved cell function in vitro and in vivo. It was shown previously that the elimination of the first 6 amino acids from the PTHrP molecule is sufficient to attenuate the cAMP/PKA-dependent processes in vitro but not in vivo [31]. It is in line with these observation that recently Safer and colleagues showed that the PTH(7-34) antagonist stimulates hair growth in mice in vivo [32]. In our previously performed experiments it was found that the N-terminal truncated PTHrP molecule had no PKC-activating domain [10]. These experiments were performed on rat myocytes. The experiments in this study show that the antagonist is not an inert molecule. Probably, there are species-dependent differences that account for this effect. However, the truncation of the first 6 amino acids shifts the cellular function of PTHrP from a cardiodepressive action into a cardioprotective one in vitro. Therefore, PTHrP antagonism may be considered as an appropriate tool in vivo. This study favours this hypothesis.

4.4. Conclusive remarks
Overall, the data from the present study suggest involvement of PTHrP in the development of heart failure in the hypertrophied heart. As the N-terminal domain of PTH and PTHrP is the part of the molecule with the highest homology, the described effect may also be related to induction of heart failure in patients with hyperparathyroidism. This study has excluded the possibility that the observed ventricular up-regulation of PTHrP is just an epiphenomenon. Nevertheless, future work is required to identify the cellular mechanisms by which PTHrP reduces cell function.


   Acknowledgements
 
The study was supported by the Deutsche Forschungsgemeinschaft (SFB 547, project A1 and DFG grant GR 729/12-1) and the BONFOR program.


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

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