Effect of cyclosporin A intervention on the immunological mechanisms of coronary heart disease and restenosis
- Authors:
- Published online on: October 4, 2016 https://doi.org/10.3892/etm.2016.3775
- Pages: 3242-3248
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Coronary heart disease (CHD) is the most common cause of mortality in Euramerican countries (1). Coronary vessels in patients with CHD undergo damage and stenosis, the abnormal narrowing of blood vessels, due to atherosclerosis (AS) (2). Coronary restenosis, additional vessel narrowing, may occur following percutaneous coronary intervention, the primary treatment for CHD, which may lead to severe complications. Dysregulation of immune responses has been shown to be an important initiating factor for the inflammatory reactions that characterize AS (3). Clinical and animal studies have suggested that the humoral and cellular immune responses of patients with CHD are in a hyperfunctional state, which may have an important role in the formation and development of atheromatous plaques in coronary arteries (3,4). Cellular immunity is mediated by T cells and involves the synergistic effects of numerous inflammatory cells and inflammatory factors. The abnormal activation of T cells has been shown to have a role during each stage in the occurrence and development of AS (5,6).
Costimulatory molecules, including cluster of differentiation (CD)40 and CD134, bind to their ligands (CD40L and CD134L) to mediate interactions between T lymphocytes and dendritic cells. These molecules have an important role in the innate and adaptive immune responses, and have been implicated in the pathogenesis of AS (7). Costimulatory molecules may also activate atheroma-associated cells to produce intercellular adhesion molecules (ICAM), cytokines, matrix metalloproteinases (MMP) and tissue factors that are involved in AS (8,9).
Cyclosporin A (CSA), which is a type of immunosuppressant that exerts its effects predominantly via the inhibition of T cell activation processes, is widely used during organ transplantation and to treat autoimmune diseases (10,11). Therefore, the present study aimed to investigate the roles of the costimulatory molecules CD40 and CD134, and inflammatory factors, in the formation and development of CHD and RS in a rabbit model, and to determine whether CSA intervention was able to attenuate the development of AS.
Materials and methods
Animals
A total of 48 healthy male New Zealand White rabbits (age, 3–5 months; weight, 2.3–3.0 kg) were randomly divided into six groups (8 rabbits/group), as follows: Normal control (N) group; N + CSA group; CHD model group; CHD + CSA group; RS model group; and RS + CSA group. The present study was approved by the ethics committee of Tianjin Chest Hospital. The N and N + CSA groups received a normal diet of vegetables and grains. The CHD and CHD + CSA groups received a 1.5% cholesterol diet and underwent iliac artery balloon injury at the end of week 4. The RS and RS + CSA groups also received a 1.5% cholesterol diet, but underwent iliac artery balloon injury at the ends of weeks 4 and 8. In addition, the N + CSA, CHD + CSA and RS + CSA groups were administered 10 mg/kg/day CSA (Novartis International AG, Basel, Switzerland) for 4 weeks by gavage. Rabbits were maintained in individual cages at temperatures of 19–25°C and 42–68% humidity, under a natural day/night cycle. Rabbits had unlimited access to water, and were sacrificed at the end of week 12 for harvesting of the iliac arteries. This was performed by inhalation of anesthesia; rabbits were administered 10 mg/ml ketamine hydrochloride at a volume of 1 ml/kg of body weight (Jiuan Wuhan Pharmaceutical Co., Ltd., Wuhan, China)
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR)
Sections of the iliac arteries were used to measure the mRNA expression levels of CD40/CD40L, CD134/CD134L and the inflammatory factors MMP-1, MMP-9, vascular cell adhesion protein (VCAM)-1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α by RT-qPCR. Briefly, total RNA was extracted from the iliac arteries and homogenized in liquid nitrogen, following which 1 ml TRIzol (Promega Corporation, Madison, WI, USA) was added. The purity and quantity of total RNA was determined using an ultraviolet spectrophotometer, and was used at a concentration of 1.08–1.752 µg/µl. Reverse transcription was conducted in a two-step reaction, as follows: i) 0.4 µl random primers, 7.6 µl double-distilled H2O and 2.0 µl RNA, incubated at 70°C for 5 min; and ii) 2.5 µl double-distilled H2O, 2.0 µl 10 µM deoxynucleotide solution, 4.0 µl 5X buffer, 0.5 µl RNase, 1.0 µl Moloney Murine Leukemia Virus Reverse Transcriptase (all Promega Corporation) at 37°C for 60 min, followed by incubating the reaction mix at 95°C for 5 min. qPCR was performed on the Applied Biosystems 7500 Real-Time PCR System (Thermo Fisher Scientific, Inc., Waltham, MA, USA) using 10.0 µl SYBR Green PCR Premix (Takara Bio, Inc., Otsu, Japan) with a reaction system consisting of 0.4 µl ROX Reference Dye II, 0.5 µl each of the forward and reverse primers, 1.0 µl cDNA (diluted 10 times), and 7.6 µl double-distilled H2O. PCR cycling conditions were 95°C for 30 sec, followed by 45 cycles of 95°C for 5 sec and 62°C for 34 sec. Primer sequences were as follows: CD40 forward, 5′-AATGCGTAGACGGCACCAAC-3′ and reverse, 5′-CAGGCATCGCTGATGCAATG-3′; CD40L forward, 5′-AACGAGAAGGGTCCTTATCC-3′ and reverse, 5′-CCAAAGTGTTGCTCATGGTG-3′; CD134 forward, 5′-CGAGGCTGTCAACTACCAAG-3′ and reverse, 5′-GTCCGCTTCCCAGCTAAGG-3′; CD134L forward, 5′-TTCTGTGCCTCACCTACGTC-3′ and reverse, 5′-CACACTGCAGGATGACGACTGAG-3′; and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) forward, 5′-GTGATGCTGGTGCCGAGTAC-3′ and reverse, 5′-GGTGGCAGTGATGGCGTGC-3′. These were provided by Beijing Liuhe Huada Gene Technology Company, Beijing, China. RT-qPCR was performed in 3 repeats. Relative mRNA expression levels normalized to GAPDH were determined using the 2−ΔΔCq method (12).
Histological analysis
Another part of the iliac arteries was used for histological analyses. Briefly, the rabbit iliac arteries were embedded in paraffin and cut into 5-µm sections. The sections were dried at 45°C for ~4 h. Following dewaxing with dimethylbenzene, the sections were treated with 3,3′-diaminobenzidine and hematoxylin and eosin. Subsequently, the sections were mounted using neutral gum and observed under a light microscope.
Immunostaining
For immunostaining, the sections were incubated with rabbit anti-CD40 monoclonal antibody (cat. no. ab58391; 1:400; Abcam, Cambridge, UK), rabbit anti-CD40L monoclonal antibody (cat. no. ab52750; 1:400; Abcam), rabbit anti-CD134 polyclonal antibody (cat. no. ab76000; 1:400; Abcam) and rabbit anti-CD134L polyclonal antibody (cat. no. ab76130; 1:400; Abcam) for 1 h at 37°C. These were then incubated with MaxVision HRP-Polymer anti-mouse/rabbit IHC Kit (Fuzhou Maixin Biotechnology Co. Ltd., Fuzhou, Fujian) for 20 min at 37°C and visualized using IHC Antibody Diluent (Fuzhou Maixin Biotechnology Co. Ltd.). The sections were observed under a microscope, and the levels of expression were analyzed using a HMIAS-2000 analysis system. The positive rate was defined as the percentage of cells with yellow or brown membranes or plasma in a high-power field. For every section, images were captured of three high-power fields to obtain a mean positive rate.
Statistical analysis
SPSS 18.0 software (SPSS, Inc., Chicago, IL, USA) was used for statistical analyses. Continuous variables are presented as the mean ± standard deviation. One-way analysis of variance was performed to compare differences among groups, while Fisher's least significant difference test was used to compare two groups. Categorical variables are expressed as percentages or frequencies. To compare count data, the χ2 test was applied, although Fisher's exact probability method was used when any form of the theory frequency was <5. Furthermore, a linear correlation analysis was performed. P<0.05 was considered to indicate a statistically significant difference.
Results
Morphology of iliac arteries
In the N and N + CSA groups, the lumens of the iliac arteries were regular, the thickness of the vessel wall was uniform, the vessel walls were thin and the inner and outer elastic plates were clear and complete. In addition, the endothelial cell nuclei were stained blue and were aligned, and the intima was shown to be predominantly composed of monolayer endothelial cells and inner elastic plate. In the N group, smooth muscle cells (SMCs) were aligned, the nuclei were fusiform and SMCs had not migrated to the endothelium (Fig. 1A and B).
The blood vessel walls of the CHD group were thicker compared with the N group, and the lumen was narrower with eccentric stenosis. Furthermore, the intima of the vessel wall was significantly hyperplastic, the inner elastic plate had a discontinuous fracture and SMCs were arranged randomly. A large number of SMCs had migrated to the endothelium and hyperplasia after breaking through the inner elastic, and had formed foam cells and fibrous connective tissue in the CHD group. The pathological appearance of the CHD + CSA group was similar to the CHD group (Fig. 1C and D).
In the RS and RS + CSA groups, the vascular lumen showed severe stenosis, with some of the lumens appearing almost entirely occluded. In addition, the intimal hyperplasia was more severe compared with the CHD group, and the hyperplastic cells were disordered in their arrangement. A large number of SMCs, phagocytes and foam cells were observed, and fibrous connective tissue and small blood vessel regeneration was apparent. The damage to the inner elastic plate was severe, while there was no clear boundary between the endangium and tunica media in the RS group (Fig. 1E and F).
mRNA expression levels of inflammatory factors
mRNA expression levels of MMP-1 were decreased in the experimental groups, as compared with the N group, although the difference was not significant (P>0.05). The mRNA expression levels of IL-6 were significantly increased in the CHD group, as compared with the N group (P<0.05); a decrease in mRNA expression levels of IL-6 in CHD + CSA and RS + CSA groups compared with the CHD and RS groups, respectively, but this was not statistically significantly different (P>0.05). The mRNA expression levels of MMP-9, VCAM-1, and TNF-α were markedly elevated in the CHD and RS groups, as compared with the N group, and the mRNA expression levels of TNF-α were significantly increased in the RS group, as compared with the N and N + CSA groups (P<0.05). Furthermore, there were significant differences in the mRNA expression levels of MMP-9, VCAM-1 and TNF-α between the CHD and CHD + CSA groups, and the RS and RS + CSA groups (P<0.05). However, as compared with the CHD group, there was no significant difference in the mRNA expression levels of any of these inflammatory factors in the RS group (Table I).
 | Table I.Relative mRNA expression levels of MMP-1, MMP-9, VCAM-1, IL-6 and TNF-α in rabbit ilial arteries (n=8/group). |
mRNA expression levels of CD40/CD40L and CD134/CD134L
As is shown in Fig. 2, the mRNA expression levels of CD40/CD40L and CD134/CD134L exhibited an increasing trend in the N, CHD and RS groups, with a significant difference among the groups (P<0.05; Table II). Notably, the relative mRNA expression levels of CD40/CD40L and CD134/CD134L were significantly decreased in the CHD + CSA group, as compared with the CHD group (P<0.05), and the same was observed for the RS + CSA group, as compared with the RS group (P<0.05; Table II). Linear correlation analysis showed that the mRNA expression levels of CD40/CD40L were positively correlated with those of CD134/CD134L (P<0.01). Specific correlation coefficients are shown in Table III.
| Table II.Relative mRNA expression levels of CD40/CD40L and CD134/CD134L in the rabbit iliac arteries (n=8/group). |
Protein expression levels of CD40/CD40L and CD134/CD134L
The rates of CD40/CD40L- and CD134/CD134L-positive cells in the vessel walls were significantly increased in the CHD and RS groups compared with the N group (P<0.05). In addition, there were significant differences in the rates of CD40/CD40L- and CD134/CD134L-positive cells between the CHD + CSA and CHD groups, and the RS + CHD and RS groups (P<0.05; Table IV).
Correlation analysis
Correlation analysis demonstrated that the mRNA expression levels of CD40/CD40L and CD134/CD134L were positively correlated with the intimal thickness, intimal area, internal elastic lamin and external elastic lamina of the rabbit iliac arteries (P<0.05; Table V). In addition, the rates of CD40/CD40L- and CD134/CD134L- positive cells were positively correlated with the intima hyperplasia index (P<0.05), but negatively correlated with the lumen area (P<0.05; Table VI).
| Table V.Correlations between the mRNA expression levels of CD40/CD40L and CD134/CD134L and neointimal proliferation and vascular remodeling. |
| Table VI.Correlations between the rates of CD40/CD40L and CD134/CD134L positive cells and neointimal proliferation and vascular remodeling. |
Discussion
CSA is a type of immune inhibitor with a high efficiency and low toxicity that is widely used in the treatment of various autoimmune diseases, aplastic anemia and other hematological diseases (13). To date, few studies have investigated the inhibitory effect of CSA on the local inflammatory responses and factors associated with the formation of AS (14,15). Therefore, the present study aimed to evaluate the effect of CSA intervention on the expression levels of local inflammatory factors in the iliac arteries of rabbit models of CHD and RS, in order to determine whether CSA exerts a protective effect against AS.
In a previous study, MMPs expressed by macrophages were shown to degrade extracellular matrix, thin the fibrous cap of plaque and promote plaque rapture (16). The expression of MMPs is regulated by numerous cytokines, although it is predominantly regulated via the induction of CD40/CD40L signaling (17,18). MMP-9 is more prevalent and has a higher activity in plaque than other subtypes of MMPs (19). Consistent with this, the present study did not demonstrate a significant difference in MMP-1 expression among the groups, except between the RS and N groups. Conversely, the expression of MMP-9 showed an increasing trend in the RS and CHD groups, as compared with the normal feeding group, thus suggesting that MMP-9 expression is upregulated during the process of AS. Notably, the expression levels of MMP-9 were significantly reduced following CSA intervention in both the CHD + CSA and RS + CSA groups.
CSA has been shown to inhibit inflammatory processes by mediating T lymphocyte inactivation and inhibiting various signaling pathways in the cytokine network. In the experimental groups, the expression levels of VCAM-1 and TNF-α were significantly decreased by CSA intervention. Cyclophilin A (CyPA) is a receptor of CSA that also participates in cellular cholesterol transport (20,21). Under the action of oxidized-low-density lipoprotein (LDL), CyPA activation may occur, which promotes cholesterol and LDL accumulation and leads to the surface expression of VCAM-1 on endothelial cells, thereby exacerbating inflammation (15). In addition, in a previous study, CyPA induced endothelial cell dysfunction and apoptosis via TNF (4). Therefore, the binding of CSA to CyPA may inhibit AS. Previous studies of organ transplantation in rats have suggested that CSA is able to downregulate the expression of TNF-α (22–24). In the present study, the relative expression levels of IL-6 were slightly reduced in the CSA intervention groups as compared with the groups that did not receive the intervention, although the difference was not significant. Conversely, a previous study reported that CSA did not reduce the serum levels of IL-6 in a rabbit model of CHD (25). The differences in these findings may be due to the animal species, animal specificity of the antibody and the total sample size used.
Costimulatory molecules, CD40/CD40L and CD134/CD134L, have an important role in the signal transduction pathway of inflammation (26). The interaction of CD40 with its ligand can induce T lymphocytes to produce cytokines, including IL-1, IL-6 and TNF-α, and to upregulate the expression of adhesion and costimulatory molecules (VCAM-1, ICAM-1, CD80 and CD86), resulting in the induction of monocytes, SMCs and endothelial cells (9,27). A combination of these inflammatory factors and CD40/CD40L interaction initiates immune responses, leading to the proliferation of endothelial cells, migration of SMCs, release of cytokines from fat cells, and the subsequent acceleration of the formation and progression of AS (27). Zirlik et al (28) demonstrated that CD40L interacts with the integrin Mac-1 on the surface of macrophages to promote the adhesion and migration of inflammatory cells. However, there is a limited number of previous studies that have investigated the association between CD134/CD134L and CHD. CD134/CD134L was shown to regulate the differentiation of T lymphocytes to promote T cell responses (29), and to induce the proliferation and differentiation of B lymphocytes to secrete immunoglobulin (30). It was suggested that the CD134L gene was an AS susceptibility gene in rats, and various genotypes of CD134L were associated with the incidence of human myocardial infarction (31). Together, these findings suggested that the interaction of CD40/CD40L and CD134/CD134L axes underlie the pathophysiological process of CHD and RS in animal models, which is consistent with the results of the present study.
CSA has been shown to inhibit protein kinase C and calcineurin, and block the expression of the CD40L gene and functioning of CD40-dependent T lymphocytes (32). Furthermore, a previous study demonstrated that CSA downregulated the expression of CD40L by inhibiting transcription factors of the nuclear factor of activated T cell family, which are substrates of calcineurin and are required for the expression of CD40L (32). Research has shown that the mitochondrial permeability transition pore (mPTP), which is closed during myocardial ischemia and open during reperfusion, may cause reperfusion injury in the open state (33). Therefore, as an mPTP blocker, CSA may attenuate reperfusion injury and improve the prognosis of patients with CHD (34). In addition, the results of the present study suggested that CSA may influence the occurrence and development of CHD via inhibition of the CD40/CD40L and CD134/CD134L axes.
The present study had some limitations. The protocol used only observed the expression of five inflammatory cytokines of local tissue and alterations in their expression levels following CSA intervention; thus, the study failed to further clarify the role of other inflammatory factors in the pathogenesis of AS and RS, and the intervention effect of CSA. Although CSA may attenuate AS by inhibiting immune responses, the underlying mechanisms remain unclear.
In conclusion, the present study demonstrated that CSA significantly decreases expression of inflammatory factors (MMP-9, VCAM-1 and TNF-α) and costimulatory molecules (CD40, CD40L, CD134 and CD134L) in humoral and cellular immune responses, which are closely associated with the occurrence of AS and CHD. It suggested that CSA intervention exerted beneficial effects on CHD and RS. These findings provide a basis for future studies, which will provide novel ideas and strategies for the prevention and treatment of CHD and RS.
Acknowledgements
The present study was supported by the Natural Science Foundation of China (grant no. 51171058), the Tianjin Science and Technology Major Program (grant no. 12ZCZDSY03200), the Tianjin Municipal Health Bureau Key Program in Science and Technology (grant no. 10KG122), and the Tianjin Municipal Health Bureau Science and Technology Foundation (grant no. 2011KZ64).
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