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Cardiovascular Research 2002 56(2):205-213; doi:10.1016/S0008-6363(02)00516-3
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Copyright © 2002, European Society of Cardiology

The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice

Wendy M Aartsena,*, Martin P Schuijtb, A.H.Jan Danserb, Mat J.A.P Daemenc and Jos F.M Smitsa

aDepartment of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Universiteit Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands
bDepartment of Pharmacology, Erasmus University Rotterdam, Rotterdam, The Netherlands
cDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Universiteit Maastricht, 6200 MD Maastricht, The Netherlands

* Corresponding author. Tel.: +31-43-388-1342; fax: +31-43-388-4149. wendy.aartsen{at}farmaco.unimaas.nl

Received 13 May 2002; accepted 10 June 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: Angiotensin II, generated from angiotensin I by angiotensin converting enzyme (ACE), induces multiple effects including vasoconstriction, positive cardiac inotropy, hypertrophy of cardiomyocytes and proliferation of fibroblasts. ACE exists both in a tissue-bound (t-ACE) and a soluble form. The functional importance of locally produced angiotensin II is still unclear. In the present study, mice lacking tissue-bound angiotensin converting enzyme (t-ACE –/–) were used to investigate the importance of t-ACE during cardiac remodeling after myocardial infarction. Methods: Mice were subjected to coronary artery occlusion or sham surgery. At 14 days after MI, stroke volume (SV) was determined with an electromagnetic flow probe around the ascending aorta. Mean arterial pressure (MAP) was measured through a cannula in the abdominal aorta. Both parameters were determined at rest and after a volume loading of 2.5 ml warm (37 °C) Ringer’s solution in 60 s. Hearts were dissected and formalin-fixed to measure infarct size, cardiac dimensions and collagen concentration. Tissue levels of angiotensin I and II were determined in hearts and kidneys. Results: At rest, under pentobarbital anaesthesia, t-ACE –/– mice (n=12) exhibited a significantly lower MAP (26±3 vs. 45±3 mmHg) than t-ACE +/+ (n=11). SV was similar in both strains. Maximal SV was significantly reduced after MI. Furthermore, infarcted t-ACE –/– (n=6) exhibited a significantly lower maximal SV compared to infarcted t-ACE +/+ mice (n=5; 20.4±1.5 vs. 29.6±2.3 µl). Structural cardiac parameters as well as cardiac and renal angiotensin II levels in t-ACE –/– and t-ACE +/+ were comparable. Conclusions: These results suggest that the structural adaptations of the heart that follow MI are independent of t-ACE. However, the presence of t-ACE is necessary for maintenance of cardiac function.

KEYWORDS Renin angiotensin system; Infarction; Remodeling; Fibrosis; Hemodynamics


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Treatment with angiotensin converting enzyme (ACE) inhibitors is a cornerstone of therapy following myocardial infarction (MI) [1]. However, the exact mechanism through which quality of life and survival are improved is still debated. Beneficial effects on cardiac contractility have even been found with low-dose ACE inhibition without reduction of blood pressure [2].

After MI, the myocyte loss is followed by invasion of inflammatory cells and fibroblasts. Collagen deposition by these fibroblasts and hypertrophy of the remaining myocytes firstly compensate for the myocyte loss but may eventually lead to heart failure [3]. During these processes both the cardiac and circulating renin–angiotensin system (RAS) activities are enhanced [4–8]. Elevated ACE levels have been shown at the site of wound healing in several tissues [9]. Also early after MI, ACE expression is found in endothelial cells, fibroblasts and macrophages [10]. Here, ACE can contribute to the local angiotensin II generation and bradykinin degradation. Both peptides can participate in the processes of inflammation and wound healing. Angiotensin II can act, independently of blood pressure, as a growth factor for cardiomyocytes and fibroblasts [11]. Bradykinin is a proinflammatory peptide [12]. Since both the AT1 receptor and the BK2 receptor are expressed at the infarction site, and blockade of either of these receptors leads to changes in cardiac wound healing [13,14], local ACE may be involved in cardiac remodeling after MI. Recently, using the tissue ACE knock out mouse model (t-ACE –/–) [15], we demonstrated a reduction in pulmonary artery remodeling after chronic alveolar hypoxia [16]. The same model was used in the present study to investigate to what extent local ACE activation contributes to the structural and functional adaptations that occur after MI.

ACE is an enzyme bound to the cell membrane that can be enzymatically cleaved producing the soluble form of ACE [17]. To investigate the role of membrane-bound ACE on cardiac function and structure after MI, we used t-ACE knock out mice generated by Esther et al. [15]. This transgenic mouse model has a genetically modified ACE gene that leads to the formation of an ACE lacking the C-terminal part of the enzyme, leaving only the N-terminal active site. Thus, only soluble ACE is expressed in mice carrying two alleles for the mutation (t-ACE –/–). T-ACE –/– mice and their wild-type littermates (t-ACE +/+) were subjected to chronic coronary artery ligation or sham surgery. Structural and functional measurements were carried out at 14 days and 3 months after MI [18,19]. No significant structural differences were found in infarcted mice lacking t-ACE when compared to their wild-type littermates. However, they exhibited a diminished functional adaptation to MI.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1 Animals
The generation of mice with a C57BL6/129/SV genetic background and lacking tissue-bound angiotensin converting enzyme (t-ACE –/–) has been described by Esther et al. [15]. Mice that were heterozygous for the mutated ACE allele (t-ACE +/–) were bred to obtain mice that were homozygous for the mutated ACE allele (t-ACE –/–) and their wild-type littermates (t-ACE +/+). All animals were housed in groups of 4–6 and had free access to standard food (SRMA-1210; Hope Farms, Woerden, The Netherlands) and tap water. The study was started when the mice were between 12 and 16 weeks old; at that time the animals weighed 26±2 g. All experiments were conducted according to institutional guidelines and conformed 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 1996).

2.2 Genotyping
To genotype the newly bred pups, a small part of the tail was cut off and genomic DNA was isolated. DNA was extracted according to the manufacturer of the Qiagen DNA isolation kit (Qiagen, Hilden, Germany). PCR analyses of the genomic DNA were performed using the primers sets described by Esther et al. [15]. Then, 1.5 µl of genomic DNA was added to the ready-to-go PCR beads (Amersham Pharmacia Biotech) diluted in 23.5 µl water containing 1.5 U Taq DNA polymerase, 10 mM Tris–HCl, 50 mM KCl, 1.5 mM MgCl2, 200 µM of each dNTP and 200 nM of each primer.

2.3 Experimental myocardial infarction
Experimental myocardial infarction was induced according to a method described previously [20]. Briefly, the mouse was anaesthetised with xylazine (5 mg/kg s.c.) and ketamine (1 mg/kg i.m.). While the mouse was fixed on its back, the trachea was intubated (1.1 mm stainless steel) to allow positive pressure respiration with room air (1.5–2 ml, 70/min). A ligature (6-0 prolene) was tied around the main left coronary artery after opening the skin, the left 4th intercostal space and the pericardial sac. Then chest and skin were closed with 5-0 silk sutures under application of gentle pressure on both side of the thorax to remove air, after which the animal was allowed to recover at 30 °C. Sham surgery was performed identically, except that the ligature around the left coronary artery was not tied.

2.4 Tissue processing
Hearts of the t-ACE mice were dissected at 14 days and 3 months after surgery. At a pressure of 100 mmHg, the animals were perfused with phosphate buffer (PBS; pH 7.4) containing 0.1 mg/ml sodium nitroprusside through a needle in the left ventricle. After 3 min, the perfusion solution was replaced by 5% formalin in PBS, which was infused for another 3 min. Heart, lung and liver were dissected and weighed, followed by formalin (10% in PBS) fixation for 24 h. The heart was then cut longitudinally through the left and right ventricles and both halves were paraffin embedded following routine histological procedures, after which 4-µm sections were prepared for morphometry.

2.5 Morphometry
Infarct size, left ventricle diameter, septum and infarct thickness were all determined using a computerized morphometry system (Quantimet 570, Leica, The Netherlands). Sections from both heart halves were stained with the AZAN technique to distinguish between collagen and heart muscle. In a section from the centre of the infarct, infarct size was measured as the percentage of the left ventricular circumference. On the same section, left ventricular circumference, septal and infarct areas were measured. Left ventricular diameter was calculated by dividing the inner circumference by {pi} assuming a circular shape for the left ventricular lumen. Septal and infarct thickness were estimated by dividing the areas by their average length [14,20].

2.6 Collagen content
Sections from both heart halves were deparaffinised and incubated in phosphomolybdic acid (0.2%) [21] for 5 min, followed by incubation with Sirius red (0.1%) in saturated picric acid solution for 90 min. After washing with 0.01 M HCl for 2 min, the sections were dehydrated and protected with coverslips. Under the microscope (magnification 400x), the collagen content was measured in the middle of the right ventricular, left ventricular and septum walls. For each area, six optical fields from both heart halves were analysed for the relative collagen content using a computerised morphometry system (Quantimet 570, Leica). Collagen present around vessels and endocardium was excluded from the total amount of Sirius red positive tissue, so only interstitial collagen was determined.

2.7 Tissue angiotensin concentrations
Adult t-ACE mice were sacrificed. Hearts and kidneys were isolated and snap-frozen in liquid nitrogen. Angiotensin (Ang) I and II were measured in cardiac and renal tissue as described previously, using SepPak extraction and high-performance liquid chromatography separation [22]. For each measurement, hearts or kidneys of 3–4 animals were pooled. [125I]Ang I was added prior to the extraction procedure, to correct for losses during extraction and separation. The concentration of [125I]Ang I and the concentrations of tissue Ang I and II in the HPLC eluate fractions were measured by gamma counting and radioimmunoassay, respectively. The lowest concentration that could be measured was 2 fmol/g for Ang I and 1 fmol/g for Ang II.

2.8 Hemodynamic measurements
Hemodynamic measurements were carried out at 14 days and 3 months after MI. The animal was anaesthetised with pentobarbital sodium (110 mg/kg i.p.), followed by intubation of the trachea (1.1 mm stainless steel) to allow positive pressure respiration with room air (1.5–2 ml, 70/min). While the mouse was lying on a heating-pad, its body temperature was kept at 37 °C. To measure mean arterial blood pressure (MAP), a saline filled catheter (PE 25) was placed in the abdominal aorta via the femoral artery and connected to a pressure transducer (micro-switch, model 156PC 156 WL, Honeywell, Amsterdam, The Netherlands). Another catheter (PE 10) was placed in the jugular vein for injections. The third right intercostal space was then opened and the ascending aorta was dissected free from the surrounding tissue. An electromagnetic flow probe (1.0 mm, Skalar, Delft, The Netherlands) was placed around the aorta just above the heart to measure stroke volume (SV) and heart rate (HR) from which cardiac output (CO) was calculated. MAP and CO were determined at rest for at least 15 min. The circulation was then loaded by infusion of 2.5 ml warm (37 °C) Ringer’s solution in 1 min and maximal values for SV and CO were recorded. Thereafter, the heart was arrested in diastole through infusion of 0.5 ml cadmium chloride (CdCl2; 0.1 M).

2.9 Statistics
Angiotensin I and II levels are shown in a box plot. Hemodynamic and histological data are shown as means±S.E.M. The impact of the genetic modification and the surgery were tested in a two-way analysis of variance, followed by Fisher’s LSD test to correct for unequal group sizes. Statistical significance was accepted if P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1 General
For the study at 14 days after MI, 35 t-ACE –/– and 24 t-ACE +/+ mice were subjected to surgery. Seven of 25 t-ACE –/– (28%) survived occlusion of the main left coronary artery whereas seven of 10 t-ACE –/– (70%) survived the sham operation. The wild-type littermates (t-ACE +/+) were less susceptible to the surgery. A total of 24 animals was subjected to surgery of which 64% (nine out of 14) survived coronary artery occlusion and 90% (nine out of 10) survived the sham surgery. All t-ACE mice that had survived surgery were used for hemodynamic measurements. One infarcted t-ACE –/– and one sham-operated t-ACE –/– died during preparation for these measurements, while four infarcted and three sham-operated wild-type littermates did not complete this procedure. HW/BW ratios from animals used in the hemodynamic measurements are summarised in Tables 1 and 3Go. Although the HW/BW ratio was increased at 14 days after myocardial infarction in both t-ACE +/+ and t-ACE –/–, these increases were not significantly different from the ratios measured in sham-operated mice. During the 3 months, HW/BW ratios increased further and became significantly different from the sham ratios in t-ACE +/+ mice, while t-ACE –/– showed a trend to increased HW/BW ratio (Table 1).


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  		Table 1 Morphometry

 

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  		Table 3 Hemodynamic parameters determined at rest

 
3.2 Morphometry
At 14 days in t-ACE +/+ mice, about 38% of the left ventricular circumference had been replaced by collagen while the infarct size in t-ACE –/– mice was only 30%. Although the t-ACE –/– mice had significantly smaller infarcts, no differences were found in left ventricular diameter, septum or infarct thickness between t-ACE +/+ and t-ACE –/– mice after 14 days MI or at 3 months after MI (Table 1).

3.3 Collagen content
After MI the left ventricular collagen content in t-ACE +/+ mice increased from 0.9±0.1 to 42±2% within 14 days and further to 66±1% after 3 months (Table 2). This increase was similar in t-ACE –/– mice. No increased collagen content was found in the right ventricle or in the non-infarcted septum.


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  		Table 2 Collagen concentration

 
3.4 Tissue angiotensin concentrations
Angiotensin I and angiotensin II concentrations measured in pooled samples (3–4 animals per sample) of t-ACE +/+ (n=13) and t-ACE –/– (n=10) hearts and kidneys are shown in Fig. 1. No differences for either angiotensin I or angiotensin II levels were found in the kidneys of both strains. Ratios for angiotensin II/angiotensin I (AngII/AngI) of t-ACE +/+ and t-ACE –/– mice were comparable (1.0±0.4 vs. 2.1±0.8, respectively). Cardiac angiotensin I and II levels were not significantly different comparing t-ACE –/– and t-ACE +/+ mice. Hearts of t-ACE knock out mice tended to exhibit a lower Ang II/Ang I ratio (0.4±1.7) than their wild-type littermates (5.9±2.8), although the difference did not reach statistical significance.


Figure 1
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  		Fig. 1 Tissue angiotensin concentrations. Each data point represents a pool of 2–4 animals. Data are presented as median and 90% confidence interval. Ang II/Ang I ratios are presented as mean±S.E.M.

 
3.5 Hemodynamic measurements
Hemodynamic parameters measured at rest and after volume load with 2.5 ml Ringer’s solution in 1 min at 14 days after MI are shown in Fig. 2. T-ACE –/– mice exhibited a significantly lower mean arterial pressure (MAP) than wild-type mice (Table 3). At rest, no significant differences were found in heart rate (HR), stroke volume (SV) or cardiac output (CO) between the four groups. In animals with MI, maximal SV after volume load was reduced. Moreover, maximal SV was significantly lower in both sham operated and infarcted t-ACE –/– mice compared to their wild-type littermates. Similar results were obtained for maximal CO (Fig. 2). Thus, MI resulted in an impaired left ventricular function which was more pronounced in t-ACE –/– than in t-ACE +/+. At 3 months after MI, the condition of both t-ACE +/+ and t-ACE –/– mice was too much impaired to cope with either the anaesthesia or the 2.5-ml volume-load. All animals died during the hemodynamic measurements.


Figure 2
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  		Fig. 2 Hemodynamic measurements. CO, cardiac output and SV, stroke volume are determined at rest and after a volume-load of 2.5 ml Ringer’s solution (37 °C) in 1 min. (Dark bars) sham-operated animals, (light bars) infarcted animals. t-ACE +/+, sham (n=6) and MI (n=5); t-ACE –/– sham (n=6) and MI (n=6), Data are presented as mean±S.E.M. tested with a two-way analysis of variance, followed by Fisher’s LSD test. {dagger}Significantly different from sham operated mice (P≤0.05). *Significant difference between MI wild-type (t-ACE +/+) and knock out mice (t-ACE –/–; P≤0.05). **Significant difference between sham wild-type (t-ACE +/+) and knock out mice (t-ACE –/–; P≤0.05).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
In the present study, the role of tissue ACE during the remodeling after MI was investigated using the tissue ACE knockout mouse model as originally described by Esther et al. [15]. The absence of tissue ACE resulted in reduced maximal stroke volume and cardiac output, which was not associated with differences in the structural adaptations.

At 14 days after MI, a significant difference was found in infarct size between t-ACE –/– and t-ACE +/+ mice. No significant differences were found in infarct size after 3 months. However, the collagen percentage in the infarct increased between 14 days and 3 months. This increase in collagen percentage might be due to early collagen synthesis followed by infarct dilation in combination with loss of cells (necrotic cells, inflammatory cells and fibroblasts), as illustrated by the increase in left ventricular diameter and decreased wall thickness. The process of wound healing involves many factors including mechanical stress, transforming growth factor-β, endothelin-1, tumor necrosis factor-{alpha} and angiotensin II [23]. In addition to influencing wound healing these regulators also influence each others expression. It might be that the lack of locally produced angiotensin II is compensated by one or several other regulators, resulting in a normal wound healing [24]. The lack of differences in the structural remodeling (morphometry and collagen content) after MI between t-ACE –/– and t-ACE +/+ mice may derive from the relatively normal tissue angiotensin II levels. Only recently, a reliable method to measure the exact tissue angiotensin I and II levels has been developed [22]. Samples from three or four mice had to be pooled due to the very low angiotensin levels in tissues and the small amounts of tissue that can be obtained from these mice. No significant differences were found in the tissue angiotensin I and II levels. The comparable angiotensin II levels found in the absence of tissue ACE may depend upon the uptake of angiotensin II from the circulation [25] or upon alternative pathways to produce angiotensin II, such as cathepsins [26] and chymase [27]. Chymase is present in mast cells, which are especially found in hypertrophied and failing hearts [28]. This suggests compensation. However, t-ACE –/– mice exhibited significantly lower plasma levels for angiotensin II [29] and a significant lower blood pressure. Although the structural adaptations were not different, t-ACE –/– mice showed reduced maximal stroke volume. This occurred in the sham operated group and became even more pronounced after MI and persisted after correction for body weight (data not shown). This observation is even more remarkable given the fact that t-ACE –/– mice had significantly smaller infarcts compared to their wild-type littermates.

The reduced maximal stroke volume in t-ACE –/– mice without differences in structural adaptation suggests that the absence of t-ACE may have an effect on compliance of the ventricle or the contractility of the myocytes. An increased cardiac collagen content impairs ventricular compliance. However, no differences were found in the collagen content of the normal or infarcted t-ACE –/– compared to t-ACE +/+ heart. Obviously, collagen is only one factor involved in cardiac compliance. Other cell–matrix structures (like fibronectin, virtonectin and intergrins) can be changed in the absence of t-ACE, leading to an altered cardiac compliance [23]. Angiotensin II has been shown to influence the myocyte contractility via several mechanisms. Angiotensin II is involved in the Ca2+ handling of the myocyte either via activation of the AT1 receptor followed by the release of intracellular Ca2+ or by increasing the myofilament affinity towards Ca2+ [30]. Indirectly, angiotensin II can have a positive inotropic effect via the induction of other neurohormones such as noradrenaline [31,32] and IGF-I [33]. Both hormones are known to stimulate the cardiac contractility [34,35]. In contrast, noradrenaline release is reduced by NO. Thus, t-ACE –/– mice might exhibit an overstimulated bradykinin-NO pathway due to the absence of t-ACE [36]. Therefore the final inotropic action of angiotensin II is an end product of complex interactions, which can be dramatically altered after myocardial infarction. Litwin et al. [37] demonstrated in rats that the intracellular Ca2+ transients changed after MI and those changes could be prevented when chronic treatment with captopril was started at 1 week after the operation. To investigate a possible time-dependent effect of the absence of t-ACE after MI, we tried to determine the cardiac output at 3 months after MI. However, at 3 months after MI both t-ACE +/+ and t-ACE –/– mice were too weak to determine the cardiac performance, suggesting that a long-term beneficial effect of t-ACE absence does not exist. With respect to the structural adaptations of the heart at 3 months after MI, again no differences were found between t-ACE +/+ and t-ACE –/– mice.

Part of the clinical beneficial effects of ACE inhibition might not be mediated through deactivation of AT1 receptors, but mediated through inhibition of bradykinin breakdown. Nolly et al. [38] demonstrated that the heart expresses a functional local kallikrein–kinin system. Enhanced activation of the bradykinin–NO pathway has several beneficial effects under ischemic conditions such as an enhanced coronary blood flow, improved cardiac metabolism and reduction of the incidence of ventricular fibrillation [39]. Furthermore, the induced production of NO is believed to have a negative influence on cell growth [40]. The fact that t-ACE –/– mice in the present study exhibited no significant difference in the hypertrophic response compared to their wild-type littermates, suggests that the bradykinin–NO pathway does not contribute to the cardiac structural remodeling after MI. Another indication for this comes from observations in mice lacking the AT2 receptor. Recent studies have shown that activation of the AT2 receptor leads to the production of NO [41]. Since the AT2 receptor is upregulated after MI and is strongly related to fibrosis [42], we investigated the role of this receptor in the early changes in cardiac dimensions and collagen content at 7 days after MI, using the same experimental procedures as described above for the t-ACE –/– mice. No differences were found in the structural parameters between mice lacking the AT2 receptor and their wild-type littermates (unpublished results).

Genetic manipulation of the ACE gene resulted in a mouse model with a specific absence of tissue ACE. Esther et al. [15] demonstrated that the ACE activity in the lung, kidney and testis of t-ACE –/– mice was undetectable. However, this model is not without limitations. The absence of t-ACE affects the blood pressure, t-ACE –/– mice have significantly lower blood pressures compared to their wild-type littermates. Also t-ACE –/– kidney function is impaired which is observed by a urinary concentrating defect. These differences in basal hemodynamics could be an explanation for the increased susceptibility of the t-ACE –/– mice towards surgery. Cardiac hemodynamics are directly related to blood pressure. Lower blood pressure may lead to a lower coronary perfusion, while it reduces the cardiac workload due to the decreased afterload. A reduction of the afterload is thought to be in favour of adequate cardiac remodeling after MI. However, despite the significantly lower blood pressure in t-ACE –/– mice, cardiac structural remodeling was similar and cardiac function was impaired, compared to t-ACE +/+ mice. Nevertheless, the fact that lack of t-ACE is associated with reduced blood pressure makes it impossible to conclude if the hemodynamic results found in this study are directly or indirectly caused by the absence of tissue ACE.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
The data derived from the present study suggest that, after MI, locally available ACE does not contribute to the early structural changes in the myocardium. However, t-ACE is involved in regulation of cardiac performance. T-ACE –/– mice do have reduced maximal stroke volume compared to their wild-type littermates, which suggests that locally available ACE contributes to the maintenance of cardiac function and is required for full compensation after MI.

Time for primary review 28 days.


   Acknowledgements
 
The authors thank Dr K.E. Bernstein for the gift of the t-ACE knock out mice. J.J.M. Debets, P.J.A. Leenders, N.J.J.E. Bitsch, M.J.A. Verluyten, R. Jaspers and R. Ceulen are gratefully acknowledged for their technical assistance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

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