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European Journal of Heart Failure 2005 7(7):1079-1084; doi:10.1016/j.ejheart.2005.03.004
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© 2005 European Society of Cardiology

The influence of oestrogen-deficiency and ACE inhibition on the progression of myocardial hypertrophy in spontaneously hypertensive rats

van Eickels Martina, Schreckenberg Rolfb, Pieter A. Doevendansc, Rainer Meyerd, Christian Grohéa and Klaus-Dieter Schlüterb,*

a Medizinische Universitäts-Poliklinik, Universitätsklinikum Bonn Germany
b Physiologisches Institut, Justus-Liebig-Universität Giessen Aulweg 129, 35392 Giessen, Germany
c Department of Cardiology, Heart-Lung Centrum Utrecht, The Netherlands
d Physiologisches Institut II, Universitätsklinikum Bonn Germany

* Corresponding author. Tel.: +49 641 9947212; fax: +49 641 9947219. E-mail address: Klaus-Dieter.Schlueter{at}physiologie.med.uni-giessen.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary Data
 References
 
Background: ACE inhibitors are widely used to antagonize the biological activity of angiotensin II in hypertensive heart disease. Oestrogen reduces angiotensin type 1 receptor expression, and thereby modifies angiotensin signalling.

Aim: To investigate the interaction of oestrogen status and ACE inhibition on the development of left ventricular hypertrophy and expression of transforming growth factor (TGF)-β1 in female spontaneously hypertensive rats (SHR).

Methods and results: Intact female SHR, ovariectomised SHR, and ovariectomised SHR with 17β-oestradiol (E2) replacement therapy were either treated with placebo or the ACE inhibitor moexiprilat. Blood pressure, left ventricular hypertrophy, and expression of TGF-β1 and TGF-β1-regulated genes were investigated. ACE inhibition reduced blood pressure in all groups. When normalised to blood pressure, a significant reduction in hypertrophy was found in ovariectomised animals receiving E2. Expression of TGF-β1 was increased in all three groups treated with the ACE inhibitor, with top levels in ovariectomised animals. Moreover, expression of ornithine decarboxylase (ODC), an adrenoceptor dependent gene, downstream of TGF-β1, was up-regulated upon ACE inhibition, except in animals which were ovariectomised and oestrogen supplemented. Parathyroid hormone-related peptide, a growth factor negatively regulated by TGF-β1, was down-regulated in all animals receiving the ACE inhibitor.

Conclusion: ACE inhibition modulated TGF-β1 and TGF-β1 dependent genes. Oestrogen deficiency alone did not influence the progression of cardiac hypertrophy in this model of female SHR.

Key Words: Oestrogen • ACE-inhibition • Hypertension • Cardiac hypertrophy • Gene-expression

Received May 25, 2004; Accepted March 3, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary Data
 References
 
Female patients suffer less frequently from cardiovascular diseases during their reproductive years than their male counterparts. This gender difference disappears after menopause, the natural state of oestrogen deficiency. Hypertensive heart disease is a common cause for the development of congestive heart failure and displays significant gender based differences [1,2]. It has been found that oestrogen modulates the progression of arterial hypertension and heart disease [3]. Moreover, it has been postulated that oestrogen replacement therapy plays a role in the progression of cardiac disease. Irrespective of oestrogen-mediated differences in the incidence of cardiac disease of both sexes, the rationale of drug treatment remains without a gender bias, i.e. in arterial hypertension, standard therapy consists of treatment with angiotensin-converting enzyme (ACE) inhibitors.

Spontaneously hypertensive rats (SHR) have been widely used as a model for hypertensive heart disease. Therefore, this model has also been employed to study the role of oestrogen on the progression of hypertensive heart disease. In particular, in these animals, the effects of oestrogen deficiency and the impact of ACE inhibition on changes in myosin composition during hypertrophy have been evaluated [4]. Furthermore, oestrogen deficiency led to an increased expression of the angiotensin type 1 (AT1) receptor in normotensive and hypertensive rats, which indicates a modification of the renin–angiotensin-system under these conditions [5]. The consequence of increased AT1 receptor levels on the influence of ACE inhibition in hypertension induced myocardial hypertrophy remains to be defined. A recent study with an ACE inhibitor showed that 17β-oestradiol is permissive for the hypertrophy reducing effect of ACE inhibition [4].

With regard to the influence of oestrogen on the development of myocardial hypertrophy in SHR and its interaction with the renin–angiotensin system (and blockade), some issues remain to be addressed. First, myocardial hypertrophy develops in SHR via a complex network in which the renin–angiotensin- and the adrenergic-system are involved. A common signalling molecule of both systems is TGF-β1, whose expression is induced by angiotensin II [6] and isoprenaline [7]. As a consequence, TGF-β1 regulates downstream targets, as indicated by induction of ornithine decarboxylase (ODC) [8]. Other paracrine growth factors, e.g. parathyroid hormone-related peptide (PTHrP), are down-regulated by TGF-β1 [9]. The latter is also regulated by oestrogen [10]. Via this signalling pathway, oestrogen is able to interfere with the progression of myocardial hypertrophy in SHR. Due to the fact that TGF-β1 is a key factor in the transition from myocardial hypertrophy to heart failure [11], we investigated the regulation of TGF-β1 in the development of myocardial hypertrophy of female SHR. For that reason, we performed experiments on the progression of myocardial hypertrophy in female SHR under basal conditions, oestrogen depletion by ovariectomy, and oestrogen replacement in ovariectomised animals. As TGF-β1 is a peptide that is released in an inactive form and requires activation by specific proteases, we decided to further analyse expressional changes of TGF-β1-dependent regulated genes, namely ODC and PTHrP. This allowed us to confirm that changes in TGF-β1 expression were of functional importance.

We further investigated the impact of ACE-inhibition on the progression of myocardial hypertrophy. The general effects of oestrogen deficiency and ACE inhibition on blood pressure, heart weight to body weight ratio, and ventricular expression of atrial natriuretic factor (ANF), as a hypertrophic marker, were analysed in comparison.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Appendix A. Supplementary Data
 References
 
Female spontaneously hypertensive rats (SHR) were put on a standard chow and were ovariectomised or sham-operated (control group) 16 weeks after birth. All groups consisted of 10 animals. For treatment, 17β-oestradiol pellets (containing 1.7 mg 17β-oestradiol, 60-day release, Innovative Research of America, Sarasota, FL, USA) were administered subcutaneously. Moexiprilat treatment was started 2 weeks after ovariectomy at 50 mgxkg– 1xd– 1 by adding the drug to the drinking water. Animals were kept under ACE inhibition for 4 weeks.

Animals were anaesthetized (100 mg/kg body wt ketamine and 5 mg/kg body wt xylazine IP), and a stretched PE catheter was inserted into the femoral artery and exteriorised at the neck. The animals were allowed to recover from anaesthesia for several days before the blood pressure measurements were performed. Measurements took place in conscious animals 5 times for 10 min each on 2 consecutive days.

The animals were anaesthetised as described above and sacrificed by decapitation. The hearts were explanted, the ventricular tissue was dissected from the heart, quickly frozen in liquid nitrogen, and homogenized according to the manufacturer's protocol to obtain total cellular RNA. 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. Expression of TGF-β1, ODC, ANF, and PTHrP was normalised to hypoxanthine-phosphoribosyl-transferase (HPRT), as housekeeping gene for loading control. The primers used in this study have been described previously [8,12].

To evaluate the amount of fibrosis, hearts from a subgroup of anaesthetised rats were arrested in diastole by intravenous injection of 1 ml 100 mmol/l CdCl2. The hearts were perfused in situ with phosphate buffered saline containing sodium nitroprusside at a pressure of 90 mm Hg to remove blood components. Thereafter, the hearts were perfused with 10% formalin in phosphate buffered saline for 10 min and were further processed for paraffin embedding. 6 µm thick cross sections from representative regions were prepared. The collagen fibres in the sections were stained with Sirius Red (0.1% wt/vol) [13,14]. The collagen content was calculated as fraction of the total area (Quantimed 570 Image Analyser, Leica Ltd, Cambridge, UK).

The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1985).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Appendix A. Supplementary Data
 References
 
3.1. Effect of oestrogen deficiency and supplementation on serum oestrogen and blood pressure
The success of oestrogen depletion by ovariectomy and of subsequent 17β-oestradiol substitution was monitored by analysing serum levels of 17β-oestradiol. These were 130.7±46.6 pmol/l in sham-operated animals, 5.9±1.7 pmol/l in ovariectomised animals (p<0.05 vs. sham, n=5), and 199.3±64.2 pmol/l in ovariectomised and 17β-oestradiol-substituted animals (n.s. vs. sham, n=5). Uterus weight was significantly reduced in ovariectomised animals compared to shams (116±10 mg vs. 515±64 mg, p<0.001, n=5) and normalised in ovariectomised animals with substitution of 17β-oestradiol (594±72 mg, n.s. vs. sham, n=5). In contrast, kidney weight was not different among the groups (shams: 2.21±0.09 g: ovariectomised animals 1.99±0.11 g; ovariectomised animals plus 17β-oestradiol: 2.23±0.11 g).

Blood pressure was evaluated in conscious animals. Blood pressure levels (6 weeks after ovariectomy) were not different between sham-operated animals and ovariectomised animals. In ovariectomised animals which received 17β-oestradiol, a significant elevation of blood pressure levels was found (Table 1).


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  		Table 1 Influence of ovariectomy, oestrogen replacement, and ACE inhibition on mean arterial pressure in female spontaneously hypertensive rats

 
3.2. Effect of oestrogen deficiency and supplementation on hypertrophy
Ventricular weights, ventricular weight to body weight ratios, and heart weight to tibia length ratios were not significantly different between sham-operated animals, ovariectomised animals, and ovariectomised animals which received 17β-oestradiol (Table 2). However, when normalised to blood pressure, ventricular weights of ovariectomised animals receiving 17β-oestradiol were significantly reduced compared to the two other groups (Table 1).


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  		Table 2 Influence of ovariectomy, oestrogen replacement, and ACE inhibition on ventricular mass of female spontaneously hypertensive rats (n=10 animals per group)

 
Ventricular ANF expression was not significantly different in sham-operated animals and ovariectomised animals. However, ovariectomised animals with 17β-oestradiol supplementation had higher ANF values, while animals which received moexiprilat displayed lower ANF values, which suggests that ANF expression is altered by humoral factors independent of hypertrophy progression (Fig. 1).


Figure 1
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  		Fig. 1 Influence of ovariectomy, oestrogen replacement, and ACE inhibition on ventricular ANF mRNA expression of female spontaneously hypertensive rats which were sham-operated (Sham), ovariectomised (OV), ovariectomised with 17β-oestradiol supplementation (OV+E2), or treated with moexiprilat (MOX) in addition. Basal expression of ANF in sham-operated animals was 14.28±1.11 (p<0.05) above the value of age matched normotensive rats. Data are means±S.E.M. from n=5 animals. *, p<0.05 vs. Sham.

 
3.3. Effect of oestrogen deficiency on ventricular TGF-β1 expression and fibrosis
Ventricular TGF-β1 expression was not significantly different between sham-operated animals and ovariectomised animals. However, ovariectomised animals with oestrogen supplementation had higher TGF-β1 values (Fig. 2, see supplementary data). Ventricular ODC expression was increased in ovariectomised animals compared to sham-operated animals and even further enhanced in animals with 17β-oestradiol supplementation after ovariectomy (Fig. 3, see supplementary data). Ventricular PTHrP expression was reduced in ovariectomised animals compared to sham-operated animals. Its expression was normalised upon substitution of 17β-oestradiol (Fig. 4, see supplementary data). Fibrosis in the ventricle, determined as the fraction of Sirius Red staining of total area was not different between the three groups (SHAM 4.4±1.3%, OV 4.5±0.7%, OV + E2 4.4±2.3%; means±S.E.M., n=5) [14].

3.4. Effect of ACE inhibition on ventricular hypertrophy
The aforementioned groups of animals also received the ACE inhibitor moexiprilat. ACE inhibition reduced blood pressure equally in all three groups (Table 1). The ventricular weight to body weight ratio was reduced in the sham-operated group (Table 2). Moexiprilat treatment equally reduced ventricular ANF expression in sham-operated animals and ovariectomised animals receiving 17β-oestradiol (Fig. 1). In contrast, in ovariectomised animals, ventricular ANF expression was not altered (Fig. 1).

3.5. Effect of oestrogen deficiency and ACE-inhibition on ventricular TGF-β1 expression
In animals treated with moexiprilat, ACE inhibition led to a significant up-regulation of TGF-β1 (Fig. 2, see supplementary data). This finding was independent of the oestrogen status, as TGF-β1 was up-regulated in all three groups. Induction of TGF-β1 was accompanied by an induction of ventricular ODC expression (Fig. 3, see supplementary data), except for ovariectomised animals on 17β-oestradiol treatment, which showed maximum values even without ACE-inhibitor treatment. Moreover, ventricular PTHrP was down regulated in all groups by moexiprilat (Fig. 4, see supplementary data), except in ovariectomised animals, which had low levels of PTHrP due to oestrogen deficiency.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Appendix A. Supplementary Data
 References
 
Our study investigated the influence of the oestrogen status on the progression of left ventricular hypertrophy in female SHR. TGF-β1 expression is involved in the transition from myocardial hypertrophy to heart failure in this model of arterial hypertension [11], therefore, we examined the ventricular expression of this growth factor. The main findings of our study are that oestrogen deficiency alone does not modify the progression of myocardial hypertrophy in young female SHR, and second, that ACE inhibition in female SHR caused an increased expression of TGF-β1.

Oestrogen deficiency in young female SHR did not change any of the classical hypertrophic signals. Ventricular weight, ventricular weight normalised to either body weight, tibia length, ventricular expression of ANF and TGF-β1, as well as fibrosis were not different between the two groups, irrespectively of a pronounced reduction in serum 17β-oestradiol and uterus weight. The only exception from this rule was the increase in ODC expression and the decrease in PTHrP expression. The latter is directly linked to the oestrogen status of the animals, as the expression was completely normalised by 17β-oestradiol replacement therapy. Such oestrogen-dependent regulation of PTHrP has been demonstrated previously in heart and other tissues [10,15].

Resubstitution of 17β-oestradiol in ovariectomised animals significantly increased blood pressure and ventricular expression of ANF, TGF-β1, and ODC. The exact mechanism by which oestrogen reduces myocardial hypertrophy has not been fully elucidated but the increased expression of ANF has been suggested to play a pivotal role [16,17,18]. This rationale has been supported by recent publications showing that ANF is not only a marker for hypertrophy but actively exerts direct antihypertrophic effects in vivo [19]. In our study, a similar correlation between ANF expression and reduction of hypertrophy was found in ovariectomised animals receiving 17β-oestradiol. It has been suggested by other investigators that TGF-β1 induces fibrosis; however, in this model, elevated TGF-β1 did not lead to myocardial fibrosis. This might be due to the fact that either the increase in TGF-β1 expression was not strong enough or TGF-β1 needs to be expressed for a prolonged time period to induce significant fibrosis.

Lowering blood pressure in young male SHR is known to antagonize the development of myocardial hypertrophy. In particular, Raasch et al. [20,24] found that the regression of left ventricular hypertrophy depends on the dose of ACE inhibitor chosen. In a low dose ACE inhibition model, no modification of left ventricular weight was detected, while in high dose treatment, both blood pressure values as well as hypertrophic indices were reduced. In addition, ACE inhibition in old male SHR was found to significantly improve survival of these animals and reduce hypertrophy and ventricular expression of TGF-β1 [20,21]. In our model, we saw a significant reduction of blood pressure which proves the effectiveness of the ACE treatment but no significant modulation of left ventricular hypertrophy. This may be due to treatment of young rather than old SHR and the duration of treatment in our study. In particular, humoral alterations have been seen in 16 week old SHR and may well play an important role in the progression of cardiac hypertrophy. Oxidative stress is a hallmark of early cardiovascular dysfunction and this phenomenon has to be attributed as an additional underlying cause of this process [22,23].

On the other hand, oestrogen is known to be permissive for the anti-hypertrophic effect of ACE inhibition in female SHR [4]. This difference between male and female SHR led us to investigate whether ACE inhibition interferes with the development of young female SHR and whether this is modified by oestrogen.

The ACE-Inhibitor moexiprilat lowered blood pressure in all groups in a comparable way. However, cardiac hypertrophy, as defined by ventricular weight to body weight ratio, was only reduced in sham-operated animals. Moreover, when normalised to blood pressure, it turned out that no pressure independent regression of hypertrophy occurred in any of the three groups, including the ovariectomised animals receiving 17β-oestradiol in which an anti-hypertrophic effect was found in the absence of ACE inhibition. Ventricular ANF expression was reduced in sham-operated animals receiving moexiprilat and ovariectomised animals receiving moexiprilat. Our study confirms a previous report on 90 days ACE inhibition in elderly female SHR in respect to the lack of an antihypertrophic effect of moexiprilat on ovariectomised animals [4].

In all three groups investigated, ventricular TGF-β1 mRNA expression was increased under ACE inhibition. These data were not validated on protein level, because TGF-β1 is released in an inactive form and needs to be activated thereafter. Immunostaining alone would have given no information whether the observed increase in TGF-β1-expression is of physiological relevance. Instead, we extended our analysis to two TGF-β1 dependent genes. As expected, ventricular ODC mRNA expression, known to require active TGF-β1, was increased in all three groups treated with moexiprilat. Also, PTHrP known to be down-regulated by TGF-β1, was found to be reduced in all these animals. The latter one is remarkable, as we have shown in this study that in the absence of ACE inhibition this factor is regulated in an oestrogen-dependent way. However, under ACE-inhibition, PTHrP is down-regulated irrespectively of the oestrogen status. The combined observation that ventricular TGF-β1 mRNA expression goes along with the expected expressional change of two completely differently TGF-β1-regulated genes underlines the physiological relevance of TGF-β1 expression.

Our study is in contrast to findings in heart failure prone SHHF/Mcc-fa rats receiving ACE inhibition in which a blood pressure lowering effect was sufficient to reduce myocardial hypertrophy [24]. However, the SHHF/Mcc-fa animals were used before blood pressure was elevated and oestrogen supplementation attenuated the increase in blood pressure. This model cannot be compared to our study in SHR. In fact, lowering of the blood pressure by ACE inhibition was not sufficient to reduce the progression of myocardial hypertrophy in young female SHR. Furthermore, as the renin–angiotensin system was antagonised under these experimental conditions, but the progression of myocardial hypertrophy was not reduced, the renin–angiotensin system does not seem to be the primary reason for the progression of myocardial hypertrophy in young ovariectomised female SHR.

In young ovariectomised female SHR, a short term reduction of blood pressure is not sufficient to reduce hypertrophy but induces the expression of TGF-β1. As the animals were treated with moexiprilat, an ACE inhibitor, the results also clearly show that the progression of myocardial hypertrophy in young female SHR is independent from the renin–angiotensin system. Although not specifically investigated in this study, the most likely mechanism by which ACE inhibition induced TGF-β1 expression is via an activation of the adrenergic system, as a consequence of baroreflex activation caused by the blood pressure lowering effect. It is in line with these suggestions, that ODC induction is known to be involved in β-adrenoceptor-dependent hypertrophy but not in other forms of hypertrophy [25]. It is also in line with these suggestions, that ODC-dependent regulation of hypertrophy by β-adrenoceptor stimulation is linked to the renin–angiotensin-system [26].


   Appendix A. Supplementary Data
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary Data
References
 
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejheart.2005.03.004.


   Acknowledgements
 
This work was supported by the Deutsche Forschungsmeinschaft, Deutsche Herzstiftung, and institutional grants by BONFOR. We like to thank M. Stimpel for the support of this study and Schwarz Pharma for providing moexiprilat.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A. Supplementary Data
 References
 

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