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Chronic chymase inhibition preserves cardiac function after left ventricular repair in rats

^a Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
^b Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan

Received 26 March 2007; received in revised form 17 September 2007; accepted 21 September 2007.

^_* Corresponding author. Address: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3780; fax: +81 75 751 4960. (Email: komelab{at}kuhp.kyoto-u.ac.jp).

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 
Objective: Although left ventricular repair (LVR) has been widely performed, the initial improvement of LV function does not last because of LV remodeling. Recent studies have demonstrated that chymase, a local enzyme in the heart, promotes angiotensin II formation as well as activation of transforming growth factor (TGF)-β, both of which facilitate myocardial fibrosis. Therefore, chymase blockade may play an important role in the prevention of cardiac remodeling after LVR. In this study, the effects of chronic chymase inhibition (Chy-I) after LVR were evaluated in a rat LV aneurysm model. Methods: Rats that developed LV aneurysms 4 weeks after coronary artery ligation underwent LVR by plicating the LV aneurysm, and were randomized into two groups, the LVR group and the LVR + Chy-I group that received an oral chymase inhibitor (10 mg/kg/day) for 4 weeks. Results: Echocardiography revealed better LV function in the LVR + Chy-I group than in the LVR group at 4 weeks. Four weeks after LVR, LV end-diastolic pressure and the time constant of LV isovolumic pressure decay, were significantly lower in the LVR + Chy-I group. The end-systolic pressure–volume relationship was higher in the LVR + Chy-I group. In the LVR + Chy-I group, mRNA expressions of TGF-β1 and BNP significantly decreased in the LV myocardium. Histology showed reduced interstitial fibrosis in the LVR + Chy-I group. Conclusions: Chronic chymase inhibition prevented myocardial fibrosis and preserved cardiac function after LVR. A chymase inhibition could be an important strategy for management after LV repair surgery.

Key Words: Chymase • Angiotensin II • Transforming growth factor (TGF)-β • Left ventricular repair (LVR) • Myocardial fibrosis

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 
Left ventricular (LV) repair (LVR) surgery after myocardial infarction (MI) has been widely performed as a surgical treatment for patients with heart failure. Early clinical studies of LVR have reported good outcomes [1], but long-term results or appropriate postoperative treatment are not well known. Actually, there have been some clinical reports on LV remodeling indicating LV dilation and functional deterioration after LVR with both linear closure and patch plasty [2]. We reported that the initial improvements of left ventricular size and function after LVR did not last long in a rat LV aneurysm model [3]. Subsequently, we have demonstrated that adjuvant therapy with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II (Ang II) type 1 receptor blocker (ARB) after LVR prevents the postoperative LV remodeling and maintains better LV function [4,5]. Chymase, an alternative pathway for the generation of Ang II, exists in the heart, and has a higher specificity for the conversion of Ang I to Ang II in humans [6]. It has been reported that cardiac chymase also promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-β (TGF-β) [7]. Considering these facts, cardiac chymase seems to play important roles in cardiac remodeling. In the present study, we evaluated the effects of chymase inhibition and investigated how chymase inhibition exerts its effects by measuring cardiac hemodynamics, cardiac chymase activity levels, and changes in the expression of molecular markers for cardiac dysfunction (brain natriuretic peptides) and fibrosis (TGF-β, collagen I, and collagen III) using a rat LVR model that we have developed.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 
Male Sprague-Dawley rats (Harlan Sprague-Dawley, weight, 290–310 g) were used in this study. The study protocol was approved by the Kyoto University Ethics Committee for Animal Research. All animals received humane care in compliance with the guidelines in the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by National Academy Press.

2.1 Surgical technique
Myocardial infarction (MI) was induced in male Sprague-Dawley rats through ligation of the left anterior descending artery as previously described [3]. In brief, the rats were anesthetized with 1% isoflurane using a volume-cycled ventilator for small animals. Anterior MI was introduced by ligation of the left anterior descending artery near the main pulmonary artery. Surviving rats developed chronic ischemic cardiomyopathy with a large LV aneurysm 4 weeks after the ligation. Before LVR, echocardiography (two-dimensional) was performed in all surviving rats with a 12-MHz phased-array transducer (Agilent SONOS 4500, Philips Medical Systems, Bothell, WA, USA) to measure infarct size. Five rats with an infarct size smaller than 30% of the LV circumference were excluded from the study because they did not show typical LV remodeling. All measurements were made by an observer blinded to the study group. Twenty rats with a large MI were randomly divided into the following two groups (n = 10 each group): LVR combined with an oral chymase inhibitor (LVR + Chy-I group) and LVR only (LVR group). LVR was performed by plicating the akinetic area of the LV as previously described [3,4]. These procedures are technically feasible. All rats survived and there was no operative mortality associated with the LVR procedure. From the following day of LVR, the rats in the LVR + Chy-I group were given 10 mg/kg/day of oral NK3201, a chymase inhibitor, mixed with their feed for 4 weeks. The NK3201 was kindly donated by Nihon Kayaku Co. (Tokyo, Japan). The LVR group was fed regular rat chow. Non-treated normal rats served as a control group (n = 6: same age as in the other two groups).

2.2 Hemodynamic measurements and echocardiography
Before and after LVR every week for 4 weeks, the measurements of mean blood pressure and heart rate and echocardiographic studies were performed under light anesthesia and spontaneous respiration as previously described in detail [3,4]. Mean blood pressure and heart rate were measured using a Softron tail-cuff without anesthesia. Echocardiography was performed as follows: rats were lightly anesthetized and placed in a supine position. Left ventricular end-diastolic dimension was measured by M-mode tracings of parasternal long axis view. LV end-diastolic area and LV end-systolic area were determined as the minimum and maximum values for tracings of the LV cavity at the level of papillary muscle in parasternal short axis view. Fractional area change (%) was calculated as (LV end-diastolic area – LV end-systolic area)/LV end-diastolic area x 100 and was used as an index of LV systolic function. Akinetic segment length (%) was calculated as (akinetic length in LV diastolic phase)/LV diastolic circumference x 100. The ratio of early to late filling velocity (E/A) of transmitral pulse-wave Doppler spectra was measured as described previously [8]. More than three measurements were taken and averaged to calculate these parameters during each examination.

2.3 Cardiac catheterization
Each rat underwent cardiac catheterization under full anesthesia and artificial ventilation for the measurement of functional parameters 4 weeks after LVR surgery as previously described [4]. A micromanometer-tipped catheter (Miller Instrument Inc., Houston, TX, USA) was inserted via the right carotid artery into the LV to measure LV end-diastolic pressure. A 3-Fr Fogarty balloon catheter (Edwards Lifesciences Co., Irvine, CA, USA) was inserted via the left femoral vein into the inferior vena cava for caval occlusion. M-mode echocardiography using a 12-MHz phased-array transducer (Agilent SONOS 4500, Philips Medical Systems, Bothell, WA, USA) was performed to calculate LV volume from end-systolic diameter and was recorded simultaneously with LV pressure both before and after balloon inflation in the inferior vena cava. End-systolic elastance was calculated from the recorded data and used as a load-independent index of LV contractility. Tau (), the time constant of LV relaxation, was calculated during the continuous LV pressure monitoring assuming a zero-pressure asymptote.

2.4 Histological examinations
Each rat was sacrificed 4 weeks after LVR after catheterization, and subjected to the following examinations. Each heart was dissected and weighed. A transverse LV slice of 2-mm thick at the level of papillary muscles was taken and was subjected to histological examination. Each slice was fixed in methanol-Carnoy's fixative and embedded in paraffin and cut into 5-µm-thick slices. After staining with azan-Mallory stain, the collagen volume fraction was determined using a computerized morphometry system, MacSCOPE Ver 2.2 (Mitani Co., Fukui, Japan). The percentage of myocardial fibrosis was obtained by calculating the mean ratio of occupied area of fibrosis in 20 separate parts of the remote area that is opposite side of the plicated region.

2.5 Molecular biological examinations
From each myocardial sample, after the slice was taken for histological examination, the apical side of the heart was subject to molecular biological examinations. The area of the plication was excised and the remaining LV myocardium was divided into two segments of the area near the LVR and the remote area that is the opposite side of the plicated region. These pieces of myocardium were frozen immediately by liquid nitrogen and stored at –80 °C until analysis. Total RNA was prepared from the frozen LV pieces of the remote area by use of TRIzol (Invitrogen, Carlsbad, CA, USA). Expressions of brain natriuretic peptides (BNP) and TGF-β1 mRNA were measured by real time polymerase chain reaction (PCR) with ABI PRISM 7700 Sequence Detector (Applied Biosystems, Foster, CA, USA) as previously described [9]. Oligonucleotides sequences used as forward primers, reverse primers and detection probes for BNP and TGF-β1 were described previously [9]. The TaqMan rodent glyceraldehydes-3-phosphate dehydrogenase (GAPDH) control reagents were used to detect rat GAPDH as the internal standard. The expression levels of the target genes were normalized by the GAPDH level in each sample.

We also measured mRNA expressions of collagen I and collagen III by conventional reverse transcription-polymerase chain reaction (RT-PCR). RT to cDNA was synthesized by analyzing 5 µg of the total RNA sample with SuperScript II reverse transcriptase and oligo(dT)_12–18 primer (Invitrogen, Carlsbad, CA, USA). The reaction was carried out in the presence of first-strand buffer, 1 mmol/l dNTPs and 20 mol/l dithiothreitol, at 42 °C for 50 min. The PCR mixture contained 1 µl of the cDNA reaction mixture, 20 pmol/l primers, PCR buffer, 0.4 mmol/l dNTPs, and 2.5 U Taq polymerase. The reaction was performed with a RoboCycler (Stratagene, La Jolla, CA, USA). Sequences of the oligonucleotide primers for PCR were as follows: collagen I sense primer, 5'-GACCGATGGATTCCAGTTCG-3', and antisense primer, 5'-TGTGACTCGTGCAGCCATCC-3', were used for the amplification of collagen I [10]; collagen III sense primer, 5'-AGATGTCCTTGATGTGCAGC-3', and antisense primer, 5'-CCACCAATGTCATAGGGTGC-3', were used for the amplification of collagen I [10]; and β-actin sense primer, 5'-CCAAGGCCAACCGCGAGAAGATGAC-3', and antisense primer, 5'-AGGGTACATGGTGGTGCCGCCAGAC-3', were used for the amplification of β-actin for the calibration of sample loading [11]. The PCR products were separated by electrophoresis on 2% agarose gel stained with ethidium bromide and the samples were then visualized by ultraviolet transillumination.

2.6 Analysis of tissue ACE and chymase activity
From each heart sample, after the slice was taken for histological examination, the basal side of the heart was subject to tissue enzyme activity. The area of the plication was excised and the myocardium in the remote area that is the opposite side of the plicated region was used for the enzyme activity. ACE and chymase activities were measured according to the methods described previously [12–14]. In brief, these tissues were minced and homogenized in five volumes (w/v) of 20 mM Tris–HCl buffer, pH 8.3, containing 5 mM Mg(CH₃COO)₂, 30 mM KCl, 250 mM sucrose, and 0.5% NP-40. The supernatant and an aliquot of the homogenates were used for the measurement of ACE and chymase activities. ACE activity in tissue extracts was measured using a synthetic substrate specifically designed for ACE, hippuryl-His-Leu (HHL) (Peptide Institute, Inc., Osaka, Japan). Chymase activity was measured by incubating the tissue extracts 5 mM Suc-Ala-Pro-Phe-4-methylcoumaryl-7-amide (Peptide Institute) as a substrate for the measurement of chymase activity in 100 mM Tris–HCl buffer, pH 8.5, containing 200 M NaCl.

	3. Statistical analysis

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 
All values are expressed as means ± SD. Comparisons of data among the multiple groups were evaluated by one-way ANOVA followed by a post-hoc analysis (Fisher's test). Statistical analyses were performed with StatView for Windows version 5.0 (SAS Institute Inc.). p < 0.05 was used as the threshold for signifying a statistically significant difference.

	4. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 
4.1 Blood pressure, heart rate, and LV function
The hemodynamic parameters and echocardiographic data are shown in Table 1 . Mean blood pressures of the LVR group and the LVR + Chy-I group were significantly lower than the control group at 1 week after LVR surgery, but there was no significant difference among the three groups at 4 weeks after LVR surgery. There was no significant difference in heart rate among the groups. Left ventricular end-diastolic dimension was not significantly different between the LVR group and the LVR + Chy-I group. Four weeks after LVR surgery, fractional area change was greater and akinetic segment was smaller in the LVR + Chy-I group than the LVR group (p < 0.05 each). By Doppler measurement, E/A of mitral inflow velocity was significantly smaller in the LVR + Chy-I group than in the LVR group (p < 0.05).

The collagen volume fraction and photomicrographs of the transverse LV slices in the two groups are shown in Figs. 1 and 2 . Severe fibrosis around the Teflon felt developed in the LVR group, whereas little fibrosis was seen in the LVR + Chy-I group. In remote areas away from the LVR region, myocardial fibrosis was also less in the LVR + Chy-I group compared with the LVR group. The collagen volume fraction based on computer analysis was significantly lower in the LVR + Chy-I group (Table 2).

View larger version (58K): [in this window] [in a new window]   Fig. 1. Azan-Mallory stained transverse section of LV 4 weeks after LVR. (A) In LVR group, severe fibrosis has developed around the pledgets. (B) In LVR + Chy-I group, small amount of fibrosis is seen around the pledgets.

View larger version (67K): [in this window] [in a new window]   Fig. 2. In the remote area of the myocardium from LVR site, representative example of fibrosis visualized with azan-Mallory stain.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Expressions of BNP and TGF-β1 mRNAs in the remote myocardium 4 weeks after LVR and normal myocardium. Levels in normal rats were arbitrarily assigned a value of 1.0; all values are mean ± SD.

View larger version (42K): [in this window] [in a new window]   Fig. 4. Expressions of collagen I and collagen III mRNAs in the remote myocardium 4 weeks after LVR and normal myocardium.

View larger version (24K): [in this window] [in a new window]   Fig. 5. ACE and chymase activities in the remote myocardium 4 weeks after LVR and normal myocardium.

	5. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

In the group with chronic chymase inhibition, fibrosis was attenuated both near and remote from the plication site, and both systolic and diastolic LV function were preserved. Moreover, the mRNA expressions of TGF-β1, BNP, collagen I, and collagen III were significantly suppressed in the remote myocardium of the LVR + Chy-I group. As previously reported, rat chymase activates TGF-β [10,15]. TGF-β is a major stimulator of tissue fibroinflammatory changes [16]. It promotes fibroblast proliferation and extracellular matrix production, particularly of collagen and fibronectin, while reducing degradation of these components [16]. TGF-β is known to induce the expression of collagen I and collagen III genes [17]. It has been reported that blockade of TGF-β by anti-TGF-β neutralizing antibody prevents myocardial fibrosis and diastolic function in pressure-overloaded rats [18]. Our findings suggested that inhibition of chymase leads to prevention of fibrosis after LVR via suppression of TGF-β activation by chymase. Matsumoto et al. reported that a chymase inhibitor decreased LV end-diastolic pressure, shortened Tau, and suppressed mRNA expressions of TGF-β, collagen I and collagen III in dogs with tachycardia-induced heart failure [19]. Together with our results, it is suggested that chronic chymase inhibition may exert favorable cardioprotective action through the suppression of fibrosis.

Another important finding of the present study is that the tissue chymase activity was remarkably augmented in chronic MI heart after LVR compared to normal heart. Matsumoto et al. also reported that the mRNA level of chymase increased in dogs with tachycardia-induced heart failure and decreased in chymase inhibitor-treated group compared with the vehicle group [19]. Moreover, treatment with chymase inhibitor leads to a reduction of tissue chymase activity as well as a reduction of fibrosis formation. Chymase inhibitor used in this study, NK3201, is a competitive inhibitor, which inhibits chymase in reversible fashion [20,21]. These findings strongly indicate pathophysiological importance of chymase in ventricular remodeling in vivo. Considering that significant fibrosis was induced in the heart after LVR, it is suggested that tissue chymase may play some roles in the fibrosis formation in vivo. From these findings, it could be suggested that in failing heart, tissue fibrosis formation is augmented via increase of chymase expression to remodel failing ventricles.

In this study, ACE activity in the LV myocardium away from the plication site was significantly higher in the LVR group than in the control group. It is well known that cardiac tissue ACE activity is increased in chronic MI model [22,23]. As we previously reported, this increase of ACE activity was not normalized even after the LVR procedure [9]. In the present study, although statistically insignificant, chymase inhibitor reduced tissue ACE activity. NK3201, used in this study, is a specific chymase inhibitor and does not inhibit ACE activity [21]. Therefore this suppression of ACE activity by NK3201 is thought to be indirect and seems to result from the improvement of cardiac function.

Nomoto et al. reported that ACE-inhibitor prevented left ventricular (LV) redilatation, attenuated enlargement of LV end-diastolic area and maintained LV systolic function, fractional area change after 4 weeks after LVR compared with non-treated group [4]. In the present study, there was no significant difference in LV end-diastolic area between the chymase inhibitor treated group and non-treated group. But fractional area change in the chymase inhibitor group was better than the non-treated group. The difference of the effects and mechanisms between ACE inhibitor and chymase inhibitor seems to be derived from depressor effects and ACE activity. There was no significant difference between in mean blood pressure at 4 weeks after LVR surgery between the LVR with chymase inhibitor group and the LVR group. In their study, systolic blood pressure in the LVR with ACE-inhibitor group was significantly lower than the LVR only group. Tsuneyoshi et al. also reported that atrial natriuretic peptide (hANP) prevented LV dilatation and preserved LV function after LVR [9]. In their study, there was no significant difference in systolic blood pressure between the hANP with LVR group and the LVR group except for 1 week after ANP infusion. But, the ACE activity in the myocardium away from the LVR site was significantly depressed in the hANP treated group compared with the LVR only group. From these facts we may say that the inhibition of ACE activity plays a crucial role in preventing late LV redilation after LVR. In the present study, chymase inhibitor did not prevent LV dilatation or suppress ACE activity. The data in the present study seems to support those above-mentioned considerations.

5.1 Study limitations
Our study has some limitations. First of all, rat chymase is different from human chymase in that it does not convert Ang I to Ang II [15]. Thus the effect of chymase inhibition might be modulated in humans because human chymase activate Ang I to form Ang II [6,7] and interacts with the renin-angiotensin system that plays a crucial role in the cardiac remodeling process. Therefore, the possible usefulness of chymase inhibition as an adjuvant therapy of ACE-I or ARB is still meaningful. The second limitation is that the LVR method in this study is not identical to the widely accepted surgical technique, called endoventricular circular patch plasty. However, in this study, the scar area was completely excluded by plication without excising any myocardium or scar tissue. We believe that this model simulates clinical LVR because of the improved LV size, shape, and function after repair.

	6. Conclusion

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 
In conclusion, the chymase may be critical for cardiac fibrosis and chronic administration of a chymase inhibitor after LVR preserves LV function by reduction of TGF-β activation and myocardial fibrosis. A chymase inhibition could be an important strategy for management after LV repair surgery.

	Footnotes

 
^\#9734; This manuscript was presented at American Heart Association scientific sessions 2005 in Dallas, Texas.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Statistical analysis 4. Results 5. Discussion 6. Conclusion References

 

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