Effect of allopurinol on cardiomyocyte apoptosis in rats after myocardial infarction
1 Department of Cardiology, The Second Affiliated Hospital of Chongqing University of Medical Sciences, Chongqing 400010, China
2 Teaching and Research Unit of Hygienic Toxicology of Chongqing University of Medical Sciences, Chongqing 400016, China
3 Department of Basic Institute of Chongqing University of Medical Sciences, Chongqing 400016, China
* Corresponding author. Tel: +86 23 63693753, Fax: +86 23 63847209, Email: qshe98{at}hotmail.com
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Abstract |
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Aims: This study was designed to explore the effect of the xanthine oxidase (XO) inhibitor allopurinol on cardiomyocyte apoptosis after myocardial infarction (MI) in a rat model.
Methods and results: MI was induced in rats by ligation of the anterior descending coronary artery. Survivors were randomly divided into three groups: sham operation group, MI group, and allopurinol group (50 mg kg–1 day–1). After 28 days, infarction size was measured. In non-infarcted zones (NIZ), apoptosis index (AI) was measured by TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated digoxigenin-conjugated dUTP nick-end labelling]; expression of Fas was detected by immunohistochemistry, and expression of XO and Caspase-3 by western blot. In addition, XO and O2–, OH-scavenging activity of myocardial tissue in the NIZ were measured by colorimetry. Results suggest that AI and expression of Fas and Caspase-3 in the NIZ were significantly depressed in the allopurinol group, compared with MI group; moreover, activity of XO was significantly decreased while O2– and OH-scavenging activity were significantly increased in the allopurinol group. Ventricular remodelling was attenuated but there were no significant differences in infarct size or XO expression levels between the allopurinol and MI groups.
Conclusion: Our results suggest that allopurinol may inhibit cardiomyocyte apoptosis in the NIZ in rats. The potential mechanism could be related to its ability to reduce reactive oxygen species and to depress the expression of Fas and Caspase-3.
Key Words: Allopurinol • Xanthine oxidase • Reactive oxygen species • Apoptosis • Myocardial infarction
Received December 12, 2007; Revised August 7, 2008; Accepted August 28, 2008
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Introduction |
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Cardiomyocyte apoptosis plays a major part in left ventricular (LV) remodelling and dysfunction after myocardial infarction (MI).1–4 The large amount of reactive oxygen species (ROS) produced in the ischaemic myocardium can induce cardiomyocyte apoptosis.3–5 Accumulating evidence suggests that there is both up-regulated expression and activity of xanthine oxidase (XO), which mediates myocardial hypertrophy and dilatation by increased production of catalytic ROS.6–9 It has been suggested that allopurinol, a potent XO inhibitor, could significantly decrease the production of ROS and thus attenuate the LV hypertrophy and dysfunction which occurs following MI.10,11 However, the effect of allopurinol on cardiomyocyte apoptosis has not been evaluated to date. Therefore, the current study sought to investigate the effect of allopurinol on cardiomyocyte apoptosis in rats after MI, and also its potential mechanisms.
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Rat models and experimental protocol
MI was induced in 50 adult male Sprague–Dawley rats weighing 180–230 g (supplied by the Experiment Animal Centre of the Third Affiliated Hospital of the Third Military Medical University, Chongqing, China), by permanent ligation of the left anterior descending coronary artery, as described previously.10 In brief, rats were anaesthetized (pentobarbital sodium; 30 mg/kg; i.p.), intubated, and mechanically ventilated with a rodent ventilator (TKR-200, Jiangxi Teli anaesthesia ventilator Co., Ltd, Jiangxi, China). After thoracotomy on the left chest, the heart was exposed. A non-vulnerarious suture line (7–0) was passed around the proximal left coronary artery and the suture was tied, successful occlusion was confirmed by visual cyanosis. The left chest was closed in three layers (ribs, muscles, and skin), 15 min after occlusion, the rats were allowed to recover from anaesthesia on their own. The 31 rats which survived the operation were randomly divided into two groups: the MI group (n = 16) and the allopurinol group (50 mg kg–1 day–1 by gavage, n = 15). Five rats that were subjected to the same surgical procedure, except for ligation of the coronary artery, served as the sham group. Allopurinol administration commenced 24 h after the operation, and continued for 28 successive days. All rat experiments were approved by the local institutional animal research committee.
Echocardiographic measurements
Transthoracic Doppler echocardiographic studies were performed with a commercially available echocardiographic system (GE Vivid 7, Fairfield, Connecticut, USA) equipped with a 13 MHz transducer. Briefly, a two-dimensional short-axis view of the left ventricle was obtained at the level of the papillary muscle, in order to record M-mode tracings. The averages of left ventricular end-diastolic dimension (LVEDD), factional shortening (FS), as well as ejection faction (EF) were calculated, on the basis of three successive cardiac cycles. The observer was blinded to the experimental group assignment.
Measurement of infarct size
After 28 days, all rats were weighed then sacrificed. The hearts were removed, and the atria, vasculature and right ventricle were dissected out. Infarct size (IS) was determined as described previously.10 In brief, sections of the left ventricle were immersed in fixative solution, dehydrated and then embedded in paraffin. Afterwards, 5 µm thick histological slices were obtained and stained with haematoxylin–eosin. Endocardial and epicardial circumferences of the infarcted tissue and the left ventricle were determined using the image analysis software (Image pro plus 4.5). IS was calculated as (endocardial + epicardial circumference of the infarcted tissue) /(endocardial + epicardial circumference of the left ventricle) and expressed as a percentage. The remaining myocardial tissue was frozen in liquid nitrogen and stored in the –80°C freezer.
Measurement of O2–, OH-scavenging and xanthine oxidase activity by colorimetry
The higher the O2–- and OH-scavenging activity, the lower the O2– and OH levels in the myocardium. According to the manufacturer’s instructions for the Superoxide Anion Free Radical Detection kit, Hydroxyl Free Radical Detection kit, and XO Detection kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China), 100 mg of the frozen myocardial tissue was made into a 10% homogenate, then the supernatant was removed and mixed with appropriate reagents. When the reactions had finished, absorbance was detected with a 752 Ultraviolet Spectrometer (Qinghua Tech-Apparatus Company, Beijing, China), in order to calculate the O2–-, and OH-scavenging activity, as well as XO activity.
In situ nick-end labelling
Apoptotic nuclei were detected by in situ TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated digoxigenin-conjugated dUTP nick-end labelling], using an In Situ Cell Apoptosis Detection Kit (MK1020, Boster Biotechnology Co., Ltd, Wuhan, China). Sections were processed in accordance with kit instructions, with modifications as noted later. In brief, a 10 min incubation in 3% H2O2 in buffer blocked endogenous peroxidase and a 10 min proteolytic digestion in prediluted proteinase K (Sigma, St Louis, MO, USA) exposed antigen binding sites. Slides were incubated in equilibration buffer for 2 min, followed by incubation in working strength TdT enzyme at 37°C for 2 h. The TdT working strength enzyme consists of TdT enzyme and digoxigenin-11-dUTP for end extension of the 3'-OH ends of double- or single-stranded deoxyribonucleic acid (DNA) of fragmented DNA. This was followed by stop/wash and anti-digoxigenin-peroxidase steps, which were performed in accordance with kit instructions. Colour was developed using 3'3-diaminobenzidine (DAB), which generated a brown reaction product. Positive Controls were prepared by treating selected slides with 0.5 mg/mL DNase I for 10 min at room temperature. dUTP labelling was not observed when TdT was omitted from the reaction. The number of apoptotic cardiomyocytes and their percentage of total cardiomyocytes were counted under a light microscope. For each slide, five fields were randomly chosen, and by using a defined rectangular field area (x200 magnification), a total of 200 cells per field were counted. The apoptotic index (AI) was determined (i.e. number of apoptotic cardiomyocytes divided by the total number of cardiomyocytes counted x 100%) from a total of 15 fields per heart, with assays performed in a blinded manner.
Agarose gel electrophoresis of deoxyribonucleic acid
To detect internucleosomal cleavage of genomic DNA, a hallmark of apoptotic cell death, DNA was isolated from LV tissue and subjected to ethidium bromide (0.4 mg/L) agarose gel (1.5%) electrophoresis.
Immunohistochemical analysis of Fas
The streptavidin–biotin complex (SABC) immunohistochemical technique was used to detect Fas using a SABC-POD kit (SA2002, Boster Biotechnology Co., Ltd, Wuhan, China). Samples were fixed within 5 min of excision in 10% neutral buffered formalin and embedded in paraffin blocks. After deparaffinization and rehydration, 10 min incubation in 3% H2O2 in buffer blocked endogenous peroxidase was performed. Slides were treated with target retrieval solution (natrium citricum buffer) at 95°C for 10 min following the manufacturer’s instructions. Non-specific binding was blocked using goat serum in PBS buffer for 20 min. Primary antibody for rat Fas (sc-7886, Santa Cruz Biotechnology, Santa Cruz, CA, USA) was applied overnight at 4°C. After the initial primary antibody incubation, slides were placed in biotinylated secondary anti-rabbit (goat absorbed) antibody for 20 min. This antibody complex was then detected by 20 min incubation in a streptavidin–biotin–horseradish peroxidase complex. Colour was developed using DAB, which generated a brown reaction product. Slides were counterstained with haematoxylin. Control slides included isotype-matched host-specific antibodies at a dilution of 1:100, 10% primary antibody host-serum, and single (no primary antibody) and double (no primary or secondary antibody) Negative Controls. For analysis of positive expression of Fas, slides were evaluated and Fas cytoplasm staining was quantified from five non-consecutive tissue sections (x200 magnification) in 10 random fields in a blinded manner. The integrated optical density (IOD) of the positively expressed area was measured as a semi-quantitative parameter with image analysis software (Image pro plus 4.5).
Western blot analysis of xanthine oxidase and Caspase-3
Equal amounts (40 µg) of protein extracts in each group were loaded and separated by SDS–PAGE using 10% acrylamide gradients. After electrophoresis, the separated proteins were transferred electrophoretically to a polyvinylidene difluoride membrane. Non-specific sites were blocked by incubation of the membrane in blocking buffer (5% non-fat dry milk in T-TBS) for 2 h. The membranes were incubated with the indicated primary antibodies [XO:(1:400), sc-20991, Santa Cruz Biotechnology, Santa Cruz, CA, USA; Caspase-3:(1:400), CPP32, NeoMarkers, USA; β-actin:(1:200), Boster Biotechnology Co., Ltd, Wuhan, China, respectively] overnight at 4°C. Horseradish peroxidase-conjugated anti-rabbit immunoglobulin IgG (1:1500, Boster Biotechnology Co., Ltd, Wuhan, China) was used as a second antibody for 2 h at 37°C. The immunoreactive bands were visualized by DAB and photographed. Absorbance analysis of the images was performed using image analysis software (Quantity One 4.4.0). The densities of XO and Caspase-3 in relation to β-actin were, respectively, expressed as XO/β-actin and Caspase-3/β-actin.
Statistical analysis
Values are expressed as mean ± SEM. All parameters were compared using a one-way ANOVA, followed, in case of significance, by a two-side Tukey test for multiple comparisons. A value of P < 0.05 was considered statistically significant.
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Echocardiography and infarct size
After 28 days, six rats in the MI group and one rat in the allopurinol group had died. All rats in the sham group survived. Compared with the sham group, LVEDD was increased and FS and EF were significantly decreased in the MI group (P < 0.01). However, LVEDD was decreased, with FS and EF significantly increased in the allopurinol group (P < 0.01), compared with that in the MI group. Although IS was smaller in the allopurinol group than in the MI group, there was no statistically significant difference between these two groups (P > 0.05), (Table 1, Figures 1 and 2). No infarct was detected in the sham group since none of the rats underwent ligation of the coronary artery.
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Cardiomyocyte apoptosis index
The apoptotic cardiomyocytes were mainly distributed in the border zones of the infarction area (Figure 3). The AI was markedly higher (P < 0.01) in the MI group and allopurinol group, when compared with the sham group (Table 1). However, the AI in the allopurinol group was significantly lower than that in the MI group (P < 0.01).
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Deoxyribonucleic acid ladder
On agarose gel electrophoresis, the DNA of the myocardial tissue in the sham group displayed a late band close to the sample well, which was recognized as the normal band pattern for cardiomyocyte DNA. The distribution of DNA fragments in the MI group was dispersed and a typical DNA ladder was observed while the relatively minor dispersion of the DNA fragments in the allopurinol group made the DNA ladder disappear (Figure 4).
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Expression of Fas
Fas expression was located on the membrane or in the cytoplasm of the cardiomyocytes, as shown in Figure 5. Compared with the sham group, the IOD of Fas was significantly higher in the MI group and the allopurinol group (P < 0.01); however, IOD in the allopurinol group was markedly lower than that in the MI group (P < 0.01), as indicated in Table 1.
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Expression of Caspase-3
The expression of Caspase-3 was similar to that of Fas, i.e. expression of Caspase-3 in the myocardial tissue was markedly increased in the MI group and the allopurinol group (P < 0.01); however, it was much lower in the allopurinol group than in the MI group, although a significant difference still existed between the allopurinol group and the sham group (P < 0.05), as shown in Table 1 and Figure 6.
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Activity and expression of xanthine oxidase
Compared with that in the sham group, XO activity in the MI group and the allopurinol group increased significantly and the expression was obviously enhanced (P < 0.01). However, XO activity in the allopurinol group decreased significantly compared with that in the MI group, while no significant difference was found in expression of XO between these two groups (P > 0.05), as shown in Table 1 and Figure 6.
O2–, OH-scavenging activity of myocardial tissue
The O2– and OH-scavenging activity of the myocardial tissue fell significantly in the MI and allopurinol groups (P < 0.01 or P < 0.05); however, these two indicators were significantly higher in the allopurinol group than in the MI group (P < 0.05), as shown in Table 1.
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Discussion |
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Allopurinol is a potent XO inhibitor, taking effect by specifically combining with XO, thereby reducing the generation of XO-derived ROS. It has been previously demonstrated that allopurinol can significantly decrease the production of ROS and attenuate the LV hypertrophy and dysfunction following MI.10,11 However, whether the improvement of ventricular remodelling by allopurinol is related to the inhibition of cardiomyocyte apoptosis has not been reported till now.
Ventricular remodelling after MI, involves expansion of the infarcted area, ventricular dilatation, as well as thinning of the ventricular wall.12–14 Our study was also designed to assess whether administration of allopurinol could affect ventricular remodelling. Echocardiography performed after 28 days showed that LEVDD was decreased while FS and EF were significantly increased in rats that had undergone the MI operation. However, there was no significant difference in IS between the allopurinol group and the MI group, which was not what we had expected. Considering the trend towards a smaller IS in the allopurinol group, we thought this might have been due to the relatively short time duration or small sample size of our study.
Growing evidence suggests that higher levels of ROS play a critical role through cellular signalling pathways, inducing apoptosis. ROS is generated intracellularly by activation of nicotinamide-adenine dinucleotide phosphate oxidase or XO, uncoupling of NO synthase, and electron transport and ‘leakage’ during oxidative phosphorylation in the mitochondria.15 Biochemical and pharmacological studies suggest that XO acts as a major source of ROS in the cardiovascular system,7 and XO-derived ROS have recently been demonstrated in experimental and clinical heart failure.6–9
Apoptosis is a distinct type of cell death characterized by a series of typical morphological events, such as shrinkage of the cell, fragmentation into membrane bound apoptotic bodies, and rapid phagocytosis into neighbouring cells without induction of inflammatory response, while the biochemical hallmark of apoptosis is internucleosomal DNA fragmentation.16 Cardiomyocyte apoptosis has recently been found in viable myocardial areas after MI in experimental and human ischaemic heart failure, and was regarded as an important factor leading to ventricular remodelling and dysfunction.15 As an independent factor, apoptosis in the expansion of the infarcted area is thought to lead to the partial ventricular wall becoming thinner and cavity dilation, i.e. early remodelling,17,18 while the apoptosis in the border and remote zones of the infarction is the main factor leading to the LV remodelling and dysfunction in the advanced stage.19
The Fas death pathway is critical for cardiomyocyte apoptosis, which is easily activated by oxidative stress.20,21 Fas ligand, an integral membrane protein, binding to a Fas trimer, can induce a conformational change in Fas that enables its cytoplasmic tail to recruit Fas-associated death domain protein (FADD) through interactions involving death domains in both molecules. FADD, in turn, recruits Procaspase-8 through homotypic interactions involving death effector motifs. The approximation of Procaspase-8 stimulates its autoactivation, following which Caspase-8 activates downstream Caspase-3 and induces apoptosis.22,23 Zhu et al.1 reported that, the conformity between the degree of Fas expression and the phase of the apoptosis increase indicated that the change in the expression of Fas was closely related to cardiomyocyte apoptosis. Researchers have confirmed that Caspase-3 is a dominated executor in the Fas death pathway, a key protease in apoptosis, which can result in DNA degradation and apoptosis by activating CAD,24 inhibiting the activity or function of Caspase-3 could depress apoptosis.25,26 Sam et al.19 reported an increase in cell death in the non-infarcted zones (NIZ) after MI along with an increase in Caspase-3 activity.
Results of this study suggest that after 28 days treatment with allopurinol, the apoptosis index (AI) and expression of Fas and Caspase-3 were remarkably reduced in rats that had undergone the MI operation. In addition, DNA ladder, a hallmark indicator of apoptosis, disappeared in these rats, suggesting anti-apoptosis activity of allopurinol in myocardial tissue in the NIZ.
The potentially cytological and molecular mechanisms by which allopurinol inhibits cardiomyocyte apoptosis have not yet been elucidated. One possible mechanism is that it relieves apoptosis by reducing LV end-diastolic pressure and mitigates the tension of the ventricular wall.27 Another possible explanation is related to inhibition of the high production of ROS in the ischaemic myocardium. The ROS (O2–, OH, H2O2, etc) which, through multiple intracellular redox signalling pathways,15,28–30 could directly damage DNA and mitochondrion, promote the expression of the redox sensitive proapoptotic genes (such as Fas, p53),31 and activate the inflammatory cytokines like mitogen-activated protein kinases32,33 to manipulate the cardiomyocyte apoptosis.34 It has been already confirmed that direct scavenging of OH or H2O2 can attenuate LV remodelling and dysfunction.35,36 Glutathione peroxidase, which removes H2O2 and detoxifies lipid hydroperoxides, has also been overexpressed in mouse heart and has been shown to ameliorate post-MI remodelling.37 XO is a potent enzymatic source of ROS, which has an up-regulated expression and activity in the ischaemic myocardium, while allopurinol and oxypurinol (its active metabolite), which are competitive inhibitors of XO, can reduce ROS production.38 Our study found that following administration of allopurinol for 28 days, XO activity was reduced and O2–, OH-scavenging activity of myocardial tissue was enhanced in rats that had undergone the MI operation; while the expression level of XO remained the same in the untreated MI group.
In summary, our results in rats indicate that following administration of allopurinol for 28 successive days, dilation of the left ventricle caused by MI was markedly attenuated; meanwhile, in the non-infarct zones XO activity was inhibited and O2–, OH-scavenging activity of myocardial tissue was enhanced by allopurinol. In addition, the AI, and expression levels of Fas and Caspase-3 were also reduced in the same area. The expression level of XO remained the same in the MI group which seems to suggest that as a potent inhibitor, allopurinol acts on the after-translation process, rather than at the transcription and translation levels. These results confirm our hypothesis that through combining with XO after MI, allopurinol could reduce the generation of ROS and inhibit cardiomyocyte apoptosis in the non-infarct zone, and prevent remodelling of the left ventricle.
Allopurinol may also inhibit cardiomyocyte apoptosis through other means, for example, by inhibiting the expression of p53,31 or by reducing the activity of the stress-activated protein kinase,39 or by inhibiting the apoptosis signal-regulating kinase 140 and so on. However, these possible mechanisms require further investigation.
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This study was partially supported by a grant from the Chongqing Natural Scientific Fund (Chongqing Committee of Science and Technology).
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The authors wish to thank Professor Yunzhen Chen for her discussions during the course of this project.
Conflict of interest: none declared.
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