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Cardiovascular Research Advance Access originally published online on September 13, 2008
Cardiovascular Research 2008 80(2):175-180; doi:10.1093/cvr/cvn250
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Deficiency of tumour necrosis factor-{alpha} and interferon-{gamma} in bone marrow cells synergistically inhibits neointimal formation following vascular injury

Hideki Murayama1, Masafumi Takahashi1,*, Masaya Takamoto2, Yuji Shiba1, Hirohiko Ise1, Jun Koyama1, Yoh-ichi Tagawa3,4, Yoichiro Iwakura5 and Uichi Ikeda1

1 Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
2 Department of Infection and Host Defense, Shinshu University Graduate School of Medicine, Matsumoto, Japan
3 Frontier Research Center, Tokyo Institute of Technology, Yokohama, Japan
4 Basic Research Programs PRESTO, Japan Science and Technology Agency, Kawaguchi, Japan
5 Institutee of Medical Science, University of Tokyo, Tokyo, Japan

* Corresponding author. Tel: +81 263 37 3352; fax: +81 263 37 2573. E-mail address: masafumi{at}shinshu-u.ac.jp

Received 4 August 2008; revised 8 September 2008; accepted 11 September 2008

Time for primary review: 11 days


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Funding
 References
 
Aims: Neointimal formation after percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Since it is now known that vascular injury involves an inflammatory response, we examined the role of tumour necrosis factor-{alpha} (TNF-{alpha}) and interferon-{gamma} (IFN-{gamma}) in the neointimal formation after injury.

Methods and results: Control (BALB/c), TNF-{alpha}-deficient (Tnf–/–), IFN-{gamma}-deficient (Ifng–/–), or double-deficient (Tnf–/–Ifng–/–) mice were subjected to wire-mediated vascular injury of the right femoral artery. Neointimal formation after injury was significantly reduced after the injury in the Tnf–/–Ifng–/– mice, compared to that in the control, Tnf–/–, and Ifng–/– mice. Immunohistochemical analysis showed that TNF-{alpha} and IFN-{gamma} were expressed in neointimal lesions in the control mice, but not in mice with deficiency of the corresponding cytokine. No significant difference in re-endothelialization was observed among these groups. The number of proliferating cell nuclear antigen in the neointimal lesions was significantly decreased in the Tnf–/–Ifng–/– mice. Bone marrow transplantation experiments revealed that deficiency of TNF-{alpha} and IFN-{gamma} specifically in bone marrow cells significantly inhibited neointimal formation after vascular injury.

Conclusion: The absence of TNF-{alpha} and IFN-{gamma} in bone marrow cells synergistically inhibits neointimal formation following vascular injury, and thus, may provide new insights into the mechanisms underlying restenosis after PCI.

KEYWORDS Bone marrow cell; Cytokine; Inflammation; Restenosis


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Funding
 References
 
Neointimal formation after vascular injury is the pathological basis of atherosclerosis and restenosis following a percutaneous coronary intervention (PCI), such as angioplasty and stenting. Although the pathogenic mechanisms have not been completely elucidated, an accumulating body of evidence suggests that inflammatory response plays a key role in these processes. Tumour necrosis factor-{alpha} (TNF-{alpha}) and interferon-{gamma} (IFN-{gamma}) are inflammatory cytokines that mediate a wide range of immune and inflammatory responses and have been found to be involved in the development of post-PCI restenosis and atherosclerosis. It has been reported that TNF-{alpha} stimulates the expression of adhesion molecules and the proliferation and migration of vascular smooth muscle cells (VSMCs), and that is up-regulated at the site of vascular injury and in atherosclerotic plaque specimens.1,2 On the other hand, IFN-{gamma} has also been shown to be expressed in vascular lesions and to regulate the expression of platelet-derived growth factor receptor-β that promotes the proliferation of VSMCs.3,4 However, the in vivo role of these cytokines remains controversial. For instance, inhibition of TNF-{alpha} by gene disruption resulted in reduced neointimal formation in a murine model of carotid artery injury.5 In contrast, the inhibition of TNF-{alpha} by neutralizing antibody had no effect on neointimal formation following vascular injury in rabbits.6 With regard to the role of IFN-{gamma}, the administration of recombinant IFN-{gamma} inhibited VSMC proliferation and neointimal formation after vascular injury.7,8 On the other hand, the inhibition of IFN-{gamma} pathway due to the overexpression of a soluble mutant of IFN-{gamma} receptor inhibited only neointimal formation after injury.9 In addition, several studies have demonstrated that TNF-{alpha} and IFN-{gamma} synergistically regulate many biological functions, including gene induction and cellular proliferation.10

In the present study, we investigated the effect of TNF-{alpha} and/or IFN-{gamma} deficiency on neointimal formation following vascular injury in mice. Recent evidence indicates a critical role of bone marrow cell-derived cytokines in the pathogenesis of restenosis and atherosclerosis;11 however, no information is available on the role of bone marrow cell-derived TNF-{alpha} and IFN-{gamma} in vascular injury. Therefore, we prepared the irradiation/bone marrow transplantation (BMT) model and determined the role of bone marrow cell-derived TNF-{alpha} and IFN-{gamma}. The findings of our study suggest the synergistic role of TNF-{alpha} and IFN-{gamma} derived from bone marrow cells in neointimal formation after injury and provide new insights into the mechanism underlying restenosis and atherosclerosis.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Funding
 References
 
2.1 Animals
The animal experimental protocol used in this study was reviewed and approved by the Shinshu University Guide for Laboratory Animals. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1996). The animals were fed a standard diet and water, and were maintained on a 12 h light and dark cycle. BALB/c mice (male, 8–12 weeks old) were purchased from Japan SLC Inc. (Hamamatsu, Japan) and used as control throughout this study. Tnf–/– and Ifng–/– mice were generated as described previously.12 Both these mutant animals were backcrossed to the BALB/c background at least 12 times. Mice with either of these two mutations were crossed to generate double-knockout mice (Tfn–/–Infg–/–).

2.2 Wire-mediated vascular injury
A wire-mediated vascular injury of the right femoral artery was produced as described previously.13 We confirmed that this procedure induced a reproducible neointimal formation in 8–12 weeks old mice.14,15

2.3 Histology and immunohistochemistry
Histological and immunohistochemical analyses were performed as described previously.11 Mice were euthanized after brief irrigation with saline to ensure that the blood was completely washed out of the femoral artery. The femoral arteries were excised from each mouse, embedded in the optimal cutting temperature (OCT) compound (Tissue-Tek; Miles Laboratories, IN, USA), and frozen in liquid nitrogen. Neointimal formation in the femoral arteries was evaluated at five locations at 100 µm intervals, with the most distal site located at the origin of branch through which a wire was inserted. The sections were stained with elastica van Gieson (EVG). To measure the intimal and medial areas, each image was digitized and analysed under a microscope (BX-51; Olympus, Tokyo, Japan) by using NIH image software ver. 1.63. The values at the five locations in each artery were averaged. All the measurements were performed in a double-blind manner by two different researchers.

For immunohistochemical analysis, arterial sections were incubated with primary antibodies against TNF-{alpha} (ab6671; Abcam, Cambridge, MA, USA), IFN-{gamma} (BioSource International Inc., Camarillo, CA, USA), CD31 (clone MEC13.3; BD Biosciences, San Jose, CA, USA), F4/80 (clone A3-1; RDI, Flanders, NJ, USA), {alpha}-smooth muscle actin ({alpha}-SMA, clone 1A4, alkaline phosphatase (AP)-conjugated; Sigma, Saint Louis, MO, USA), and proliferating cell nuclear antigen (PCNA, Dako Cytomation, Glostrup, Denmark). This was followed by incubation with biotin-conjugated secondary antibodies. Next, the sections were washed and treated with avidin-peroxidase (ABC kit; Vector Laboratories, Burlingame, CA, USA). The reaction was developed using the DAB Substrate Kit (Vector Laboratories). Vector Red AP substrate kit was used for {alpha}-SMA staining. The sections were then counterstained with haematoxylin. No signals were detected when species- and isotype-matched immunoglobulin (Ig)G (Vector Laboratories) was used instead of the primary antibody as a negative control. Quantitative staining for CD31, F4/80, and {alpha}-SMA was quantified independently performed in a double-blind manner by at least two researchers.

2.4 Bone marrow transplantation
Bone marrow-transplanted mice were developed as described previously.11,14 Whole bone marrow cells from the control and Tfn–/–Infg–/– mice were harvested by flushing their femurs with phosphate-buffered saline (PBS). Red blood cells were lysed with ammonium chloride potassium buffer (150 mM NH4Cl, 10 mM KHCO3, 0.1 mM ethylenediaminetetraacetic acid; pH 7.2) at 4°C for 20 min. They were washed three times with PBS and resuspended in 0.5 mL PBS. Recipient mice (control and Tfn–/–Infg–/– mice, 6–8 weeks old) were lethally irradiated with a total dose of 9 Gy (MBR-155R2, Hitachi, Japan) and injected with bone marrow cells through the tail vein. To verify the reconstitution of bone marrow after transplantation by this protocol, we used green fluorescent protein (GFP)-transgenic mice (kindly provided by Professor M. Okabe, Osaka, Japan) as donors. Flow cytometry analysis revealed that at 6 weeks after transplantation, peripheral blood cells consisted of more than 90% GFP-positive cells. By using this protocol, we produced three types of bone marrow-transplanted mice: control to control (BMTCont->Cont) mice, Tfn–/–Infg–/– to control (BMTTnf–/–Ifng–/–->Cont) mice, and control to Tfn–/–Infg–/– (BMTCont->Tnf–/–Ifng–/–) mice.

2.5 Statistical analysis
Data are expressed as mean ± SEM. The unpaired two-tailed t-test was used to compare the two groups. For comparisons between multiple groups, we determined the significance of the differences between the means of the groups by using one-way analysis of variance, followed by the Tukey–Kramer procedure for comparison of means. All analyses were performed using StatView software (Abacus Concepts Inc., Berkeley, CA, USA). Differences with P-values of <0.05 were considered to be statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Funding
 References
 
3.1 Expression of tumour necrosis factor-{alpha} and interferon-{gamma} in neointimal lesions
We next examined whether TNF-{alpha} and IFN-{gamma} were expressed in the neiointimal lesion after injury. The expression of TNF-{alpha} and IFN-{gamma} was clearly visualized in the neointimal lesion at 28 days after injury by using immunohistochemical analysis (Figure 1). As expected, TNF-{alpha} was not expressed in Tnf–/– and Tnf–/–Ifng–/– mice, and IFN-{gamma} was not expressed in Ifng–/– and Tnf–/–Ifng–/– mice.


Figure 1
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  		Figure 1 Expression of TNF-{alpha} and IFN-{gamma} in neointimal lesion. Wire-mediated vascular injury was produced in the control, Tnf–/–, Ifng–/–, and Tnf–/–Ifng–/– mice. The femoral arteries were excised at 28 days after injury. Immunohistochemical staining for TNF-{alpha} and IFN-{gamma} was performed. Representative photographs are shown (n = 3). The arrowheads indicate the internal elastic lamina. The bar represents 50 µm.

 
3.2 Effects of tumour necrosis factor-{alpha} and/or interferon-{gamma} deficiency on neointimal formation following injury
We first investigated whether TNF-{alpha} and/or IFN-{gamma} deficiency influenced the development of neointimal formation after wire-mediated vascular injury. EVG staining showed marked neointimal formation in the control mice at 28 days after vascular injury (Figure 2A). Although neointimal formation did not significantly differ between the control mice and Tnf–/– or Ifng–/– mice, that in the Tnf–/–Ifng–/– mice was significantly reduced. Quantitative analysis showed that the neointimal area and intima/media (I/M) ratio were reduced; however, no significant difference was observed in the medial area between Tnf–/–Ifng–/– mice and the other three types of mice (Figure 2B–D).


Figure 2
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  		Figure 2 Effect of TNF-{alpha} and/or IFN-{gamma} deficiency on neointimal formation. Wire-mediated vascular injury was produced in the control (n = 10), Tnf–/– (n = 18), Ifng–/– (n = 18), and Tnf–/–Ifng–/– (n = 14) mice. The femoral arteries were excised at 28 days after injury. The sample sections were stained with EVG, and neointimal formation was evaluated. (A) Representative photographs of EVG staining. The arrowheads indicate the internal elastic lamina. The bar represents 100 µm. (B–D) The bar graphs show the neointimal area (B), medial area (C), and I/M ratio (D) calculated using the NIH image software. Data are expressed as mean ± SEM. *P < 0.05.

 
3.3 Detection of endothelial cells, macrophages, and vascular smooth muscle cells
Since we previously demonstrated that early re-endothelialization following vascular injury inhibits neointimal formation,14 immunohistochemical analysis of the endothelial marker CD31 was performed. No significant difference was observed in the re-endothelialization after injury among these mice (Figure 3A and B). Further, we performed immunohistochemical analysis to detect macrophages (F4/80) and VSMCs ({alpha}-SMA), and assessed the cellular contents of neointima in the mice. Consistent with previous reports,13,16 our finding was that the neointimal lesion was composed of many VSMCs and some macrophages (Figure 3A). The number of macrophages and VSMCs per unit neointimal area did not differ among the mice (Figure 3C and D).


Figure 3
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  		Figure 3 Detection of endothelial cells, macrophages, and VSMCs. Wire-mediated vascular injury was produced in the control, Tnf–/–, Ifng–/–, and Tnf–/–Ifng–/– mice. The femoral arteries were excised at 28 days after injury. (A) Immunohistochemical staining for endothelial cells (CD31), macrophages (F4/80), and VSMCs ({alpha}-SMA) was performed. Representative photographs are shown. The bar represents 100 µm. (B–D) The bar graphs show the re-endothelialization (B), F4/80-positive cells (C), and {alpha}-SMA-positive area (D) in the neointimal lesions. Data are expressed as mean ± SEM (n = 4 for each).

 
3.4 Proliferation activity in neointimal lesions
Neointimal lesions after vascular injury mainly comprise proliferative VSMCs; we determined their proliferation activity in vivo by immunohistochemical staining for PCNA. The number of PCNA-positive cells significantly decreased in the neointimal lesions in Tnf–/–Ifng–/– mice compared to that in the control mice (Figure 4).


Figure 4
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  		Figure 4 Proliferation activity in neointimal lesion. Wire-mediated vascular injury was produced in the wild-type and Tnf–/–Ifng–/– mice. The femoral arteries were excised at 28 days after injury. Immunohistochemical staining for PCNA was performed. (A) Representative photographs of PCNA staining are shown. The arrowheads indicate the internal elastic lamina. The bar represents 50 µm. (B) The bar graph shows the number of PCNA-positive cells in the neointimal lesion. Data are expressed as mean ± SEM (n = 4 for each). *P < 0.05.

 
3.5 Role of bone marrow cell-derived tumour necrosis factor-{alpha} and interferon-{gamma} in neointimal formation
To assess the role of bone marrow cell-derived TNF-{alpha} and IFN-{gamma} in neointimal formation after vascular injury, we produced three types of bone marrow-transplanted mice (BMTCont->Cont mice, BMTTnf–/–Ifng–/–->Cont mice, and BMTCont->Tnf–/–Ifng–/– mice) and evaluated neointimal formation following injury. The formation of neointima following vascular injury in BMTCont->Cont mice tended to be reduced when compared with that in the wild-type mice (no irradiation) (Figure 5A and B). Moreover, neointimal formation in BMTTnf–/–Ifng–/–->Cont was significantly decreased when compared with that in BMTCont->Cont (I/M ratio, P < 0.01) and BMTCont->Tnf–/–Ifng–/– (P < 0.05). These results indicate that TNF-{alpha} and IFN-{gamma} in bone marrow cells are critical for neointimal formation following vascular injury.


Figure 5
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  		Figure 5 Contribution of bone marrow cells to neointimal formation. Bone marrow-transplanted mice [BMTCont->Cont (n = 7), BMTTnf–/–Ifng–/–->Cont (n = 6), and BMTCont->Tnf–/–Ifng–/– mice (n = 6)] were developed, and wire-mediated vascular injury was produced in them 8 weeks after BMT. The femoral arteries were excised at 28 days after injury. The sample sections were stained with EVG and neointimal formation was evaluated. (A) Representative photographs of EVG staining. The arrowheads indicate the internal elastic lamina. The bar represents 100 µm. (B and C) The bar graphs show the neointimal area (B), medial area (C), and I/M ratio (D). Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Funding
 References
 
The major findings of this study are as follows: (i) neointimal formation following vascular injury was significantly reduced in the Tnf–/–Ifng–/– mice compared to that in the control, Tnf–/–, and Ifng–/– mice. (ii) Immunohistochemical analysis revealed the expression of TNF-{alpha} and IFN-{gamma} in the neointimal lesions in control mice, but not in the lesions in mice with deficiency of the corresponding cytokine. (iii) No significant difference in re-endothelialization was observed among these groups. (iv) The number of proliferating cells, as determined by PCNA staining, in the neointimal lesion was significantly decreased in Tnf–/–Ifng–/– mice. (v) Deficiency of TNF-{alpha} and IFN-{gamma} specifically in bone marrow cells significantly inhibited neointimal formation after vascular injury. These findings indicate the synergistic role of bone marrow cell-derived TNF-{alpha} and IFN-{gamma} in neointimal formation after vascular injury and provide new insights into the mechanism underlying post-PCI restenosis and atherosclerosis.

Increasing evidence indicates the importance of inflammatory responses in the pathogenesis of restenosis and atherosclerosis. Although TNF-{alpha} and IFN-{gamma} are inflammatory cytokines and have been shown to be involved in this pathogenetic process, the precise role of these cytokines is controversial. Furthermore, the synergistic induction of atherogenic genes by TNF-{alpha} and IFN-{gamma} has been demonstrated;10 Indeed, TNF-{alpha} and IFN-{gamma} have been shown to synergistically induce many atherogenic genes, such as those encoding adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)], inflammatory cytokines/chemokines [interleukin (IL)-6, IL-8, regulated on activation, normal T expressed and secreted (RANTES), monokine-induced by IFN-{gamma} (Mig), and IFN-{gamma}-inducible protein (IP-10)], nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidases), and inducible nitric oxide synthase (iNOS).10 The molecular mechanism of the synergistic effect appears to involve the interaction of transcription factors, such as TNF-{alpha}-activated nuclear factor-{kappa}B (NF-{kappa}B), with IFN-{gamma}-activated signal transducer and activator of transcription 1 (Stat-1) or interferon regulatory factor-1 (IRF-1). Our finding that double deficiency of TNF-{alpha} and IFN-{gamma} synergistically inhibited neointimal formation after injury may also support these observations; however, further investigations are required to elucidate its precise mechanism.

We clearly demonstrated that bone marrow cell-derived TNF-{alpha} and IFN-{gamma} are critical for neointimal formation after vascular injury. Previously, several investigators showed that the expression of TNF-{alpha} and IFN-{gamma} is upregulated in the injured arteries at the early phase of vascular injury.5,6,9 Furthermore, recent investigations have also demonstrated the contribution of bone marrow cells to neointimal formation after injury;11,16 however, the precise role of bone marrow cells has not yet been fully understood. Our data suggest the critical role of bone marrow cells as a cellular source of TNF-{alpha} and IFN-{gamma}. On the basis of our findings, we postulated the mechanism responsible for neointimal formation after injury as follows: (i) vascular injury directs bone marrow-derived cells such as monocytes and lymphocytes to the injury site in the artery; (ii) the accumulated bone marrow-derived cells secrete inflammatory cytokines such as TNF-{alpha} and IFN-{gamma}; and (iii) secreted TNF-{alpha} and IFN-{gamma} cytokines initiate the migration and proliferation of VSMCs, thereby resulting in neointimal formation. Thus, bone marrow-derived TNF-{alpha} and IFN-{gamma} could be therapeutic targets for the prevention of restenosis and atherosclerosis.

Several limitations of this study should be noted. First, gene disruption in mice might compensate for the loss of signalling pathways by altering the expression of other proteins although no information about such compensation in Tnf–/– and Ifng–/– mice is available. Second, the model used in this study is not a reliable experimental model of human PCI because the injury was produced on a normal non-atheromatous artery. Third, irradiation has been reported to cause many deleterious effects on recipient animals, such as inhibiting cellular proliferation and inducing apoptotic cells death.17 In fact, Tanaka et al.18 recently demonstrated that the neointimal formation following vascular injury in irradiated bone marrow-transplanted mice was less than that in non-irradiated mice and suggested that bone marrow-transplanted mice may not always represent a physiological process that occurs naturally in response to injury in non-irradiated mice. Consistent with their findings, we also observed reduced neointimal formation after injury in BMTCont->Cont mice, suggesting that other models (e.g. parabiosis model18) might be useful for exploring the precise role of bone marrow-derived cells.

In conclusion, we showed that double deficiency of TNF-{alpha} and IFN-{gamma} synergistically inhibited neointimal formation after vascular injury. Particularly, the absence of these cytokines in bone marrow cells plays a critical role in the inhibition of the progression of neointimal formation. Our results indicate the importance of the synergistic effect of TNF-{alpha} and IFN-{gamma} in bone marrow cells and that these cytokines are novel therapeutic targets for restenosis and atherosclerosis.


   Funding
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Funding
References
 
This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology (to M.T.), the Ministry of Health, Labor and Welfare (to M.T. and U.I.).


   Acknowledgements
 
We thank Junko Nakayama, Yuka Ichihara, and Kazuko Miiswa for technical assistance, and Shinsuke Taki (Shinshu University Graduate School of Medicine) for valuable suggestions.

Conflict of interest: none declared.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Funding
 References
 

  1. Tanaka H, Sukhova G, Schwartz D, Libby P. Proliferating arterial smooth muscle cells after balloon injury express TNF-alpha but not interleukin-1 or basic fibroblast growth factor. Arterioscler Thromb Vasc Biol (1996) 16:12–18.[Abstract/Free Full Text]
  2. Rus HG, Niculescu F, Vlaicu R. Tumor necrosis factor-alpha in human arterial wall with atherosclerosis. Atherosclerosis (1991) 89:247–254.[CrossRef][Web of Science][Medline]
  3. Harvey EJ, Ramji DP. Interferon-gamma and atherosclerosis: pro- or anti-atherogenic? Cardiovasc Res (2005) 67:11–20.[Abstract/Free Full Text]
  4. Zohlnhofer D, Richter T, Neumann F, Nuhrenberg T, Wessely R, Brandl R, et al. Transcriptome analysis reveals a role of interferon-gamma in human neointima formation. Mol Cell (2001) 7:1059–1069.[CrossRef][Web of Science][Medline]
  5. Zimmerman MA, Selzman CH, Reznikov LL, Miller SA, Raeburn CD, Emmick J, et al. Lack of TNF-alpha attenuates intimal hyperplasia after mouse carotid artery injury. Am J Physiol Regul Integr Comp Physiol (2002) 283:R505–R512.[Abstract/Free Full Text]
  6. Zhou Z, Lauer MA, Wang K, Forudi F, Zhou X, Song X, et al. Effect of anti-tumor necrosis factor-alpha polyclonal antibody on restenosis after balloon angioplasty in a rabbit atherosclerotic model. Atherosclerosis (2002) 161:153–159.[CrossRef][Medline]
  7. Hansson GK, Holm J. Interferon-gamma inhibits arterial stenosis after injury. Circulation (1991) 84:1266–1272.[Abstract/Free Full Text]
  8. Castronuovo JJ Jr, Guss SB, Mysh D, Sawhney A, Wolff M, Gown AM. Cytokine therapy for arterial restenosis: inhibition of neointimal hyperplasia by gamma-interferon. Cardiovasc Surg (1995) 3:463–468.[CrossRef][Medline]
  9. Kusaba K, Kai H, Koga M, Takayama N, Ikeda A, Yasukawa H, et al. Inhibition of intrinsic interferon-gamma function prevents neointima formation after balloon injury. Hypertension (2007) 49:909–915.[Abstract/Free Full Text]
  10. Paludan SR. Synergistic action of pro-inflammatory agents: cellular and molecular aspects. J Leukoc Biol (2000) 67:18–25.[Abstract]
  11. Yajima N, Takahashi M, Morimoto H, Shiba Y, Takahashi Y, Masumoto J, et al. Critical role of bone marrow apoptosis-associated speck-like protein, an inflammasome adaptor molecule, in neointimal formation after vascular injury in mice. Circulation (2008) 117:3079–3087.[Abstract/Free Full Text]
  12. Tagawa Y, Sekikawa K, Iwakura Y. Suppression of concanavalin A-induced hepatitis in IFN-gamma(–/–) mice, but not in TNF-alpha(–/–) mice: role for IFN-gamma in activating apoptosis of hepatocytes. J Immunol (1997) 159:1418–1428.[Abstract]
  13. Sata M, Maejima Y, Adachi F, Fukino K, Saiura A, Sugiura S, et al. A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. J Mol Cell Cardiol (2000) 32:2097–2104.[CrossRef][Web of Science][Medline]
  14. Yoshioka T, Takahashi M, Shiba Y, Suzuki C, Morimoto H, Izawa A, et al. Granulocyte colony-stimulating factor (G-CSF) accelerates reendothelialization and reduces neointimal formation after vascular injury in mice. Cardiovasc Res (2006) 70:61–69.[Abstract/Free Full Text]
  15. Shiba Y, Takahashi M, Yoshioka T, Yajima N, Morimoto H, Izawa A, et al. M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system. Arterioscler Thromb Vasc Biol (2007) 27:283–289.[Abstract/Free Full Text]
  16. Tanaka K, Sata M, Hirata Y, Nagai R. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res (2003) 93:783–790.[Abstract/Free Full Text]
  17. Sindermann JR, Verin V, Hopewell JW, Rodemann HP, Hendry JH. Biological aspects of radiation and drug-eluting stents for the prevention of restenosis. Cardiovasc Res (2004) 63:22–30.[Abstract/Free Full Text]
  18. Tanaka K, Sata M, Natori T, Kim-Kaneyama JR, Nose K, Shibanuma M, et al. Circulating progenitor cells contribute to neointimal formation in nonirradiated imeric mice. FASEB J (2008) 22:428–436.[Abstract/Free Full Text]

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